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theres alot of diseases out there that seem to share some main common factors. I

can't but fell theres some common threads involved when it comes to damage of

the nervous system. and very possably the same cause.

toxin exposure. this was on a word pad so I can only post the whole thing.

SECTION A.1 – ELECTRICAL IMBALANCE IN AUTISM

A. Evidence of Electrical Imbalance in Autism

This entire section of my theory is the most technical and difficult. If you

don't understand everything discussed, and most people won't, don't worry about.

Skip over stuff that makes your head hurt. As long as yet get the gist that an

electrical imbalance seems implicated in autism, you will be able to move onto

the next section and still follow the train of my thoughts.

1. Brief Description of Nervous System

The human nervous system, including the brain, is largely an electrical system.

It functions by electrical currents passing along its wires, which are

specialized cells called neurons that connect to each other at junctions called

synapses. Synaptic activity is controlled by chemicals called neurotransmitters.

You have probably heard of several neurotransmitters, such as dopamine,

serotonin and nor-adrenaline. These are just a few of many neurotransmitters

that tune the nervous system.

Like any electrical system, such as a computer or a stereo, the human nervous

system functions through the control of how electrical signals propagate through

the system. This is largely controlled by neurotransmitters through their

influence on neural excitation or inhibition. Every neurotransmitter is either

excitatory or inhibitory. This means that they either accelerate and increase

the amplification of a propagating signal or they dampen, diminish or divert the

signal. Two neurotransmitters are particularly important in this regard.

Glutamate is the brain's primary excitatory neurotransmitter, constituting

about 50% of the total volume of neurotransmitters in the brain. GABA is the

brain's main inhibitory neurotransmitter, constituting on average about 35% of

total neurotransmitter volume in the brain. The brain maintains a very careful

homeostatic balance between these two neurotransmitters, as they are both

crucial to human function. Glutamate causes electrical signals to propagate

through the nervous system, turning the system on and allowing for advanced

functions such as consciousness, thinking, learning and memory.

GABA keeps the electrical system properly tuned, channeling and restraining

electrical excitation to allow normal human brain function. When GABA is in the

normal range in the brain, we are not overly aroused or anxious. At the same

time, we have appropriate reactions to situations in our environment. GABA is

the communication speed controller, making sure all brain communications are

operating at the right speed and with the correct intensity. Too little GABA in

the brain and the communication becomes out of control, overstimulated, and

chemically unstable. Too much GABA and we are overly relaxed and sedated, often

to the point that normal reactions are impaired.

Excessive neural excitation can result either from too much glutamate or too

little GABA. Either way, the normal homeostatic balance between excitation and

inhibition is thrown off in favor of greater levels of excitation. While high

levels of excitation can be positive, since glutamate induced neural excitation

is responsible for much of the learning and memory skills people have, a balance

shifted too far in favor of excitation can have serious consequences. Seizures

involve a local breakdown in excitatory balance; too much excitation occurs and

electrical spasms, seizures, result. Excitotoxicity is neural cell death as a

result of too much excitation. A detailed discussion of glutamate and GABA in

autism is contained in the addendum to this Section.

2. Evidence of Electrical Imbalance

Scientists know that many different conditions and exposures can cause people

to develop autistic behaviors. Several genetic diseases including fragile X

syndrome, Rett syndrome, Down syndrome, Angelman syndrome, tuberous sclerosis,

and epilepsy greatly increase the chance a child will develop autism.

Environmental insults can also cause a person to develop autism. For instance,

poisoning with methyl mercury can cause the person exposed to develop behaviors

that appear autistic. Fetal exposure to alcohol greatly increases the odds of

autism diagnoses in infants.

Upon learning the multiplicity of convergent causes of autistic behaviors in

the early development of my theory of autism, a question began to form in my

mind – what do all of these genetic conditions and environmental exposures have

in common? The answer is electrical imbalance.

a. Specific Evidence

There is significant evidence of electrical imbalance in the autistic nervous

system.

1) Seizures

One commonality between these causes of autism involves seizures. About a third

of people with autism have regular seizures, though many think this estimate to

be low because mild seizures are often not diagnosed and seizures that do not

result in jerking or flailing are often not recognized as such. Mercury

poisoning often causes seizures and convulsions. So does fetal alcohol syndrome.

Seizures are common in fragile X syndrome (15-20% of males have them), Rett

syndrome (very common), Angelman syndrome (80% have seizures), tuberous

sclerosis (common) and Down syndrome (5-10% have seizures). Epilepsy is a

condition primarily characterized by the presence of seizures. The level of

epilepsy in autistic children is much higher than in normal persons. This

indicates that some type of electrical imbalance may tie all of these conditions

together.

2) Abnormal EEG's

Abnormalities seen in EEG's, along with the frequency of seizures in autistic

persons, were among the earliest pieces of evidence of a biologic basis for

autism. Abnormal EEG's were found in 65% of 147 autistic children when repeated

EEG's were done according to Small in 1975. Another study of autistic

individuals showed that 540 of 889 (60.7%) subjects had abnormal EEG

epileptiform activity in sleep. The most frequent sites of epileptiform

abnormalities were localized over the right temporal region. 50-70% of autistic

individuals have ongoing `sharp-spike' activity documented in sleeping EEG; this

suggests that these children have noisy and unstable cortical networks. There is

a higher incidence of abnormal EEG's in mentally retarded autistic individuals

but a significant amount of abnormal EEG's were also found in the mildly and

non-retarded autistic persons. The level of abnormality scaled with the severity

of the condition.

A question arises as to, if electrical imbalances is at the core of autism, why

don't all children show abnormal EEG's all the time. What may be happening is

that the autistic brain is not always overstimulated. It has the potential for

overstimulation, but it may be relaxed and quiescent at many times. It may only

be when stressors are present, and noradrenaline and/or cortisol are flowing,

that the brain waves are pushed into abnormal and/or epileptiform shapes. This

will vary in all persons with autism. Also, we know that depending on the state

of alertness of the child and the number of recordings, the chance of an

abnormal EEG changes significantly. With a greater number of recordings, there

is a greater frequency of abnormal EEGs. Abnormal EEG's have been found more

frequently when recordings included states of sleep, awake and drowsiness,

instead of just one or two states.

3) Abnormal Processing of Sensory Information

Sensory processing is ultimately an electrical process. Information about the

external world is picked up by sensors in the peripheral nervous system (eyes,

touch sensors) and transmitted up the spinal cord, through the hindbrain, and

into the processing centers of the brain to be distributed by the thalamus.

Sensory processing problems indicate abnormalities in this electrical system.

Sensory defensiveness, an over reaction to sensory information, indicates that

the problem involves a failure of the peripheral nervous system and brain to

adequately filter and modulate the mountains of sensory information that flow

into the brain, most of which is extraneous to our survival and is simply

discarded by a normally functioning nervous system.

Although not listed as a symptom in DSM IV, the tool used by doctors to assess

mental conditions like autism, sensory processing abnormalities are highly

consistent symptoms of autism. Most often, the abnormality is manifest as

sensory defensiveness. This defensiveness is most often seen in the auditory and

tactile senses. However, it shows up with visual and gustatory processing, as

well as in temperature regulation and other internal senses. There is some

scientific support for this sensory processing abnormality. EEG studies reveal a

pattern of abnormally distributed response in autism during tasks that demand

selective attention. Also, both in children and in adults, physiological

measures suggest that perceptual filtering in autism occurs in an all or none

manner, with little specificity in selecting for the location of the stimulus.

4) Abnormal Prepulse Inhibition

Prepulse Inhibition (PPI) is a neurological phenomenon in which a weaker

pre-stimulus (prepulse) inhibits the reaction of an organism to a subsequent

strong startling stimulus (pulse). The reduction of the amplitude of startle

reflects the ability of the nervous system to temporarily adapt to a strong

sensory stimulus when a preceding weaker signal is given to warn the organism.

Deficits of prepulse inhibition manifest in the inability to filter out the

unnecessary information; they have been linked to abnormalities of sensorimotor

gating. Such deficits are noted in patients suffering from illnesses like

schizophrenia and Alzheimer's disease

Adults with autism have sensorimotor gating deficits similar to other

neurodevelopmental disorders, implicating a failure of normal inhibitory

regulation of sensory, motor, and attentional mechanisms. Lower prepulse

inhibition was correlated with increased ratings of restricted and repetitive

behaviors. The absence of an effect of prepulse amplitude suggests abnormal

sensory responsiveness – a possibility supported by skin conductance findings of

abnormally high tonic arousal and abnormally high phasic response to stimuli in

autism. Similar findings of high arousal and high responsiveness in Fragile X

Syndrome support that idea that these abnormal sensory phenomena may be markers

of abnormal neural development.

5) Excessive Negative Association

Everyone experiences associations. When a neutral and a strong aversive

stimulus are experienced simultaneously, the aversive stimulus will frequently

create an association with the neutral stimulus, such that in the future the

neutral stimulus is perceived by the nervous system as negative. This is part of

how the human brain learns, through the pairing of electrical stimuli which

cause the strengthening of synaptic connections, with glutamate being the

neurotransmitter that mediates this process.

There is significant evidence that autistic individuals are much more sensitive

to this pairing of associations. Stimuli that would not be considered negative

by a normal person may be sufficiently aversive to an autistic individual that

many neutral objects become negatively colored. This provides many more

opportunities than normal for negative paired associations to develop, which are

very hard for most people who care for those with autism to identify or

understand. This may account for some of the fear reactions that are generated

in autistic individuals as they navigate through the world. An explanation for

why this occurs may be that an excessively excitatory brain more easily creates

conditioned responses because of the interaction of excess neural excitation at

the brain's synapses and the abnormal flow of sensory information to the brain.

b. General Evidence

Observations related to heightened levels of seizure and abnormal EEG in autism

have led a group of scientists to develop the hypothesis that:

Autism is fundamentally a glutamatergic disorder driven by altered synaptic

excitation/inhibition ratios in crucial neural systems that underlie sensation

and behavior, with dysregulation primarily a function of deficits in inhibition

of behavior by the cortex.

In my theory, autism can result from too much glutamate, as well as too little

GABA in crucial neural circuits, or both, and there is substantial evidence of

one such abnormality in essentially every single vector cause of autism, whether

genetic or environmental.

Neural hyperactivity resulting from excessive levels of glutamate has clearly

been implicated as a primary cause of the seizing activity in epilepsy.

Importantly, glutamate imbalances are present in fragile X syndrome, Rett

syndrome, Angelman syndrome, tuberous sclerosis and Down syndrome, all of which

are associated with high risk of autism. This is also true in several single

vector environmental causes of autism. For instance, mercury poisoning causes

seizures by destroying glial cells in the brain. Glial cells are the most

important cell type in the brain other than neurons. Glial cells generally

support the neurons helping them do their jobs. One specific function for a

class of glial cells called astrocytes is to assist in the reuptake

(reabsorption) of glutamate at neural synapses. If astrocytes are damaged by

methyl mercury, which preferentially lodges in astrocytes after crossing the

blood-brain barrier, and can't help with reuptake, this results in too much

glutamate hanging around in a portion of the brain causing excessive levels of

excitation. This causes seizures in persons with mercury poisoning and death of

brain cells through excitotoxicity. I believe it also causes the symptoms of

autism.

In addition, inadequate levels of GABA have been implicated in other genetic

conditions and environmental exposures that result in autistic behaviors. For

instance, prenatal exposure to thalidomide and valproic acid has been shown to

dramatically increase the chance an infant will develop autism. Both of these

chemicals inflict their damage, at least in part, by reducing the number of GABA

dominated (highly inhibitory) synapses in an important portion of the brain

called the cerebellum, a structure that provides an electrical filtering role

for the brain, controlling and attenuating sensory information flowing up the

peripheral nervous system.

Even more importantly, as discussed in detail in the appendix to this section,

imbalances in the balance between glutamate and GABA have been shown in numerous

studies of persons with autism who do not have other identifiable conditions

that could have caused the autistic behaviors. This imbalance has involved both

too much glutamate and too little GABA. It is clear that excess glutamate alone

can result in neural hyperexcitability. Researchers believe that decreased

GABAergic inhibition could also lead to a glutamatergic hyperexcitation, which

can have many effects including subsequent damage to vulnerable target neurons,

a mechanism considered to be relevant for onset of diverse neurological

illnesses.

c. A Potential Conclusion

A logical conclusion from this evidence is that excess excitation caused by an

imbalance of neurotransmitters in the brain may be a significant part of the

mechanism of action in autism. People who suffer from genetic diseases which

result in such an imbalance tend to develop autistic behaviors. People who are

exposed to an environmental toxin like mercury which acts to tip the balance to

excitation also tend to develop autistic behaviors. Both groups of people tend

to experience seizures and other types of spasming, abnormal EEG's, sensory

processing abnormalities, and abnormal prepulse inhibition, indicative of a

problem with the homeostatic mechanisms of the nervous system. So do people with

diagnosed autism without an identifiable cause.

B. Theories of Neural Imbalance in Autism and Other Conditions

Bad things happen when the balance between inhibition and excitation in the

nervous system is thrown off. To quote Dr. Everly:

(T)he phenomenology of many chronic anxiety and stress related diseases is under

girded by the existence of a latent common denominator, existing in the form of

a neurological hypersensitivity for excitation (or arousal) residing within the

subcortical limbic circuitry.

I am not alone in arguing for a primary role for imbalance in neural excitation

in psychological disorders.

1. Everly's Disorders of Arousal

More specifically, Everly has argued that an ascending neural overload (too

much information flowing up the peripheral nervous system to the processing

centers of the brain) may be responsible for creating unorganized and

dysfunctional discharges of neural activity that are manifested in persons with

insomnia, undefined anxiety, depressive behavior, and in some cases manic

behavior patterns lacking direction or apparent purpose. Everly seems to view

neurological arousal and excitation as the same phenomenon.

This neural hypersensitivity results in the conditions that he calls disorders

of arousal. I think that Dr. Everly is correct and that his neural sensitization

model is also at the core of autism – autism is also a disorder of arousal, or

excitation. And, there are other researchers who have reached similar

conclusions related to autism. But, this is far from an accepted theory of

autism. Everly, and the researchers cited below, are not in the mainstream of

the autism debate.

According to Dr. Everly, this neural sensitization phenomenon may be based on

one or more of six mechanisms: 1) augmentation of excitatory neurotransmitters,

2) declination of inhibitory neurotransmitters, 3) augmentation of brain

structures, especially the amygdala and the hippocampus, that regulate fear and

stress responses through excitation and inhibition, 4) changes in the

biochemical bases of neuronal activation through genetic and intracellular

means, 5) increased neuromuscular arousal, and 6) repetitive cognitive

excitation.

At the core of Everly's synthesis is the interaction between the human stress

response and neural balance in the brain. In support of his model, Everly cites

three different researchers who have created a theoretical basis for how stress

plays a role psychological and physiological distress – Gellhorn, Weil and

Malmo. Their theories are different but have much overlap.

According to Gellhorn, in the waking state the ergotropic division of the

autonomic nervous system ( " ANS " ) is dominant and responds primarily to

environmental stimuli. If these stimuli are very strong or follow each other at

short intervals, the tone and reactivity of the sympathetic nervous system

( " SNS " ) increases. Both extremely intense and acute sympathetic stimulation or

chronically repeated, intermittent lower level sympathetic stimulation, both of

which can be environmental in origin, can lead to SNS hyperfunction. Such

sympathetic activity creates a condition of sympathetic neurological

hypersensitivity which serves as the neurological predisposition associated with

the psychophysiological symptoms observed in anxiety, stress, and related

disorders of arousal.

Weil, from a somewhat different viewpoint, notes that two major processes can

be effective in charging the arousal system: 1) high intensity stimulation

and/or 2) increased rate of repeated stimulation. Gellhorn's and Weil's theories

agree that hypersensitivity of the nervous system (i.e. a lowered threshold for

activating limbic, autonomic, and hypothalamic effector systems) can be achieved

through environmental stimulation and proprioceptive stimulation when presented

in either an acute and intense (trauma like) manner or in a lower level yet

chronically repeated exposure pattern. Once achieved, such a status of lowered

activation threshold could serve as a self-sustaining neurological basis for

emotional and psychophysiological disorder.

Malmo and his colleagues found that select groups of individuals who possessed

arousal disorders, such as anxiety, seemed to demonstrate somewhat higher

baseline levels of muscle tension when compared with non-patients. More

importantly, upon the presentation of a stressor stimulus, the muscle tension of

the patient population reached higher levels of peak amplitude and subsequently

took significantly longer to return to baseline levels once the stressor was

removed. This phenomenon was interpreted by Malmo of being indicative of a

defect in homeostatic mechanisms following arousal in such patients.

Other researchers have established a neurological concept called kindling,

which represents one of the most popular models of brain plasticity and

neurological hypersensitivity in clinical literature. Kindling is a term

originally conceived of to identify the process by which repeated stimulation of

limbic system structures leads to a lowered threshold for convulsions / seizures

and to a propensity for spontaneous activation of such structures, with

resultant affective lability, ANS hyperfunction, and behavioral disturbances.

Kindling-like processes have been implicated in a host of behavioral and

psychopathological conditions. Shader has stated, with regard to anxiety

disorders, that one might speculate that kindling processes could increase

attack-like firing from a source like the locus ceruleus activating center.

Redmond and Huang support such a conclusion by suggesting that panic disorders

are predicated on a lowered firing threshold at the locus ceruleus. Such

discharge could then arouse limbic and cortical structures on the basis

adrenergic efferent projections rising from the locus ceruleus. Monroe has

provided evidence that certain episodic behavioral disorders may be based on a

kindling like limbic ictus (a sudden event like a seizure). He notes that as it

is known that environmental events can induce synchronized electrical activity

within the limbic system, this also provides an explanation of an ictal illness.

Monroe implicates explosive behavioral tirades, impulsively destructive

behavior, extreme affective lability, and episodic psychotic behavior in such a

neurological dysfunction. According to other researchers, long term augmentation

of the locus ceruleus pathways following trauma underlies the repetitive

intrusive recollections and nightmares that plague patients with post traumatic

stress disorder.

Other researchers have gone farther and argued that kindling and relative

sensitization models may be useful conceptual approaches to understanding the

development of psychopathology in the absence of seizure discharges. They report

data that demonstrate the ability of adrenaline and dopamine agonists to

sensitize animals and humans to behavioral hyperactivity and especially

affective disorders. They refer to this phenomenon as behavioral sensitization

rather than kindling because non ictal status is obtained as an end point.

Rather, the achieved end point represents a lowered depolarization threshold and

an increased propensity for spontaneous activation of limbic and related

circuitry.

Whatever the biological alteration underlying the neuronal plasticity

associated with limbic system neurological hypersensitivity, Everly reports that

the phenomenon 1) appears to be inducible on the basis of repeated, intermittent

stimulation with the optimal interval between stimulations to induce kindling

being about 24 hours, 2) appears to last for hours, days and even months, 3)

appears to show at least some tendency to decay over a period of days or months

in the absence of continued stimulation if the initial stimulation was

insufficient to cause permanent alteration (like with PTSD, not with autism),

and 4) appears to be inducible on the basis of environmental, psychosocial,

pharmacological and / or external electrical stimulation.

Everly has concluded that it would seem reasonable that in order for a

therapeutic intervention to work effectively to ameliorate these disorders of

arousal, it should work in such a way as to neurologically desensitize and

reduce overall activity within the limbic circuitry. This can be achieved by 1)

reducing excitatory neurotransmitter responsivity, 2) reducing neuromuscular

arousal, and 3) reducing cognitive excitation.

2. Researchers Who Reached Similar Conclusions with Autism

A number of research groups investigating autism have reached conclusions

similar to Everly's theory of disorders of arousal.

a. stein and Merzenich

stein and Merzenich hypothesize that at least some forms of autism are

caused by a disproportionately high level of excitation (or disproportionately

weak inhibition) in neural circuits that mediate language and social behaviors.

A more excitable (more weakly inhibited) cortex is, by its nature, more poorly

functionally differentiated; this type of cortex will lead to broad ranging

abnormalities in perception, memory, and cognition, and motor control. Moreover,

a noisy (hyperexcitable, poorly functionally differentiated) cortex is

inherently unstable, and susceptible to epilepsy. An imbalance of excitation and

inhibition could be due to increased glutamatergic signalling or to a reduction

in inhibition due to a reduction in GABAergic signalling. They note that Hussman

has earlier suggested that suppressed GABAergic inhibition is a common feature

of the autistic brain.

stein and Merzenich have also postulated that imbalances in excitation vs.

inhibition can be amplified by maturational processes that result in delayed

synapse maturation or in abnormal myelination. In the developmental process,

synapse maturation and progressive myelination contribute crucially to the

generation of more coherent activities in forebrain networks and systems, and

thereby to the progressive strengthening of cortical signalling (to the

progressive reduction of cortical process noise).

b. Belmonte, Corchesne et al

Another group of researchers have similarly argued that anatomical and

functional abnormalities in autism suggest that its core dysfunction may involve

some pervasive alteration of neural processing. One route to such an alteration

might be via abnormally low signal-to-noise in developing neural assemblies, a

condition that may be produced by abnormal neural connectivity. They note that

the high incidence of epilepsy in autism is consistent with this hypothesis, and

that there has been no shortage of relevant neuropathological findings. The

numbers of Purkinje cells, and to a lesser extent granule cells, in cerebellar

cortex are abnormally low, presumably leading to disinhibition of the cerebellar

deep nuclei and consequent overexcitation of thalamus and cerebral cortex. It is

important to note that a decrease in signal-to-noise can arise from

abnormalities of connectivity in either direction: an overconnected network

passes so much noise that it swamps the signal, and an underconnected network

passes so little signal that it becomes lost in the noise. In either case, large

segments of the network are connected to either an all on or all off state, and

the network's information capacity is thereby reduced.

Belmonte, Corchesne et al postulate that a failure to delimit activation within

an abnormally connected network may be observable as hyperarousal in response to

sensory input, and decreased ability to select among competing sensory inputs.

Cardiovascular, neuroendocrine, and neurochemical indices of arousal in novel

and stressful situations are consistent with this prediction, as are

physiological and behavioral observations of the extent and intensity of

perceptual processing. Physiologically, functional imaging has demonstrated

heightened activity in brain regions associated with stimulus driven, sensory

processing, and decreased activity in regions that normally serve higher order

processing.

c. Brock, Brown, Boucher and Rippon

This group proposed in 2002 that autism is associated with abnormalities of

information integration that is caused by a reduction in the connectivity

between specialized local neural networks in the brain and possible

over-connectivity within the isolated individual neural assemblies. They

supplemented this in 2007 with an argument that orchestration of the balance

between excitation and inhibition is a key aspect to the successful coordination

of the coupling between local and distant neural assemblies in the brain. Unless

an appropriate signal to noise ratio is sustained, the output of any network may

not be sufficiently robust or distinct to successfully achieve the necessary

processing.

d. Researchers Implicating GABA in Arousal Dysfunction

There are several other research groups who have reached conclusions that

autism involves dysregulation of excitatory balance in the brain, which

necessarily results in `disorders of arousal' as described by Everly. These

groups have focused on the action of GABA in the brain.

1) Hussman

It has been suggested by Hussman that autism is the result of an imbalance of

the excitatory glutamatergic and inhibitory GABAergic pathways, resulting in

overstimulation in the brain and inability to filter out excess stimuli from

environmental and intrinsic sources. In his model, suppression of GABA

inhibition results in excessive stimulation of glutamate specialized neurons and

loss of sensory gating. Hussman postulates that GABA inhibition may become

defective through multiple etiological factors. Loss of inhibitory control may

cause deterioration in the quality of sensory information due to the failure to

suppress competing `noise' resulting in compensatory restrictions in sensory

input to a narrow, repetitive, or controllable scope. Also given the high

comorbidity of autism with epilepsy and seizures, Hussman has suggested that a

similar molecular etiology could exist between the disorders.

2) Dhossche et al

Dhossche et al. believe that autism is the result of an adverse cascade of

events that stems from one or more genetic / environmental insults. Over time,

if uncompensated, the cascade leads to adverse conditioning of stress adaptation

networks and results in various interrelated developmental, psychological,

neurological and immunological pathologies, including autism.

Dhossche et al. have set forth criteria that they believe necessary for the

formulation of a comprehensive theory of autism. Any viable theory must consider

the changeable nature of symptoms, course, and outcome in autistic people, and

should account for a) the early onset of clinical abnormalities, B) worsening of

symptoms around puberty in a considerable number of patients, c) association

between autism and epilepsy, and d) genetic transmission of the disorder.

According to Dhossche, there is substantial evidence that central GABA

dysfunction can account for these key features.

a. GABA is the main inhibitory neurotransmitter in the mature brain; 25-40% of

all terminals contain GABA. In early development, GABA has an excitatory trophic

role affecting neuronal wiring, plasticity of neuronal network, and neural

organization. Interference with the trophic role of GABA may affect development

of neuronal wiring, plasticity of neuronal network, and neural organization.

b. Decreased GABA inhibition in the hypothalamus is considered an important

trigger for onset of puberty. Adaptive changes in GABA function at the onset of

or during puberty may worsen or induce disorders associated with underlying

abnormalities of GABA function. Increased rates of seizure disorders, catatonia,

and worsening of autistic symptoms or overall behavioral deterioration have been

reported in people around and after puberty.

c. GABA has been strongly implicated in epilepsy. About 30% of autistic people

develop some type of epilepsy.

d. Genetic studies have implicated the proximal long arm of chromosome 15 in

autism and catatonia. The most common chromosomal abnormality in autism is an

alteration in chromosome 15q11-13, a region that contains three GABAA receptor

subunit candidate genes for autism (GABRB3, GABRA5, and GABRG5). This is the

same chromosome location that includes the Prader-Willi Syndrome / Angelman

Syndrome region.

Dhossche sets forth other evidence which implicates GABA in autism: 1) reports

of decreased numbers of cerebellar GABAergic Purkinje cells especially in the

posterior lobe, 2) decreased levels of key synthesizing enzymes (GAD65 and

GAD67) in the cerebellum and parietal cortex, 3) neuropathology in the deep

cerebellar nuclei, many cells of which are GABAergic, 4) decreased density of

GABAA receptors and benzodiazepine binding sites in the specific subfields of

the hippocampus formation, and increased packing density of parvalbumin labeled

GABAergic interneurons in the CA3 and CA1 subfields, and 5) elevated plasma GABA

in autistic children aged 5-15 years. These and other findings related to GABA

are discussed in the Appendix below.

APPENDIX TO SECTION A.1

This appendix will discuss evidence of glutamate and GABA abnormalities in

autistic individuals generally, not focused on those whose autism resulted

specifically from a chromosomal defect or environmental exposure. It is highly

technical and not necessary for a lay person to read in order to be prepared to

understand the next Section of this paper.

1. Glutamate / GABA Imbalance in Autism

Despite their pervasiveness in brain activity and function, GABA and glutamate

have received very little attention in the study of autism as well as other

conditions like bipolar disorder. This is starting to change. Researchers

working in various labs have found abnormalities in various components of the

glutamate and GABA systems, including the levels of the neurotransmitters

themselves, the number of receptors for the neurotransmitters, the chemical that

converts glutamate to GABA, and the chemicals, neuroligins and neurexins, that

affect the development of synapses at which glutamate and GABA are released.

2. Glutamate and Autism

a. Circumstantial Evidence of Glutamate Involvement

Several lines of circumstantial evidence suggest the involvement of glutamate

in autism: 1) symptoms of hyperglutamatergia mimic the behavioral phenotypes of

autism; 2) serotonin receptor 2A agonists cause behavior similar to autism,

perhaps because of reduced expression of serotonin 2A receptors on glutamatergic

inhibiting GABAergic neurons, 3) associated studies have implicated the

involvement of GABAA receptors on genes that in turn modulate glutamatergic

function, 4) excessive glutamatergic activity is associated with epileptiform

activity, which is highly associated with autism, and 5) glutamate activity

peaks during the second year of life, which is a time when autism symptoms

emerge. If this system is hyper-functional, it is possible that neuronal growth

and connectivity are damaged during critical periods of development.

b. Experimental Findings Regarding Glutamate

Since researchers only recently started investigating glutamate in autism,

partially because effective ways of measuring glutamate have only recently been

developed, the experimental findings are limited.

1) Plasma Neurotransmitter Levels

One study measured plasma amino acid levels in fourteen autistic children, all

below 10 years of age. All affected children had low levels of glutamine and

asparagine. Eleven children had increased aspartic acid and eight children had

high levels of glutamate; seven of these children had a concomitant increment of

taurine. In another study investigating glutamatergic involvement in autism,

serum levels of glutamate in the patients with autism were significantly higher

than those of normal controls. In contrast, serum levels of other amino acids

(glutamine, glycine, d-serine, l-serine) in the patients with autism did not

differ from those of normal controls.

2) Glutamate Transporter Gene

Upregulated expression of the glutamate transporter gene was found in

postmortem studies of autistic brain tissue.

3) Impact of Anti-Epileptic Drugs

In a recent study, 8 of 13 subjects given lamotrigine for intractable epilepsy

showed a decrease in autistic symptoms. Lamotrigine attenuates some forms of

cortical glutamate release via inhibition of sodium channels, P- and N-type

calcium channels, and potassium channels.

4) Impact of Atypical Anti-psychotic Drugs

One mechanism of action underlying the relative efficacy of atypical

antipsychotics, such as risperidone, for autism may be the suppression of

glutamate release via 5-HT2A antagonism.

5) Impact of NMDA Antagonist Drug

A recent study looked at amantadine (an antagonist of the NMDA subtype receptor

but also with anti-cholinergic effects) in 39 subjects with autism. While

significant improvements were noted on clinician rated scores for hyperactivity

and inappropriate speech, non difference from placebo was noted for parents'

measures.

6) Receptors

In one study, the mRNA levels of several genes were significantly increased in

autism, including excitatory amino acid transporter 1 and glutamate receptor

AMPA 1, two members of the glutamate system. Abnormalities in the protein or

mRNA levels of several additional molecules in the glutamate system were

identified on further analysis, including glutamate receptor binding proteins.

AMPA-type glutamate receptor density was decreased in the cerebellum of

individuals with autism.

3. GABA and Autism

Researchers have worked much more extensively on the GABA system related to

autism, and the evidence strongly suggests that it is heavily involved. The

authors of the textbook " GABA in Autism " have concluded that GABA inhibitory

transmission systems are genetically altered in autism. A seminal work on stress

related disorders has concluded that:

GABA is the major inhibitory neurotransmitter responsible for sensory gating of

stress-related information that influences behavioral, endocrine, and autonomic

networks. It has long been suspected that the GABA filtering process is

compromised in many autistic children. Impairment of the GABA system could

overwhelm the brain with sensory information, leading to many of the behavior

traits associated with autism.

There is much evidence of GABA abnormalities of many different types in autism.

a. Decreased GABA Levels in Autism

One of the most consistent findings in autism, discussed below in detail, is a

reduction in the size of several structures of the cerebellum, including the

Purkinje cell layer and the deep cerebellar nuclei. Both of these cerebellum

elements are highly GABAergic.

Also, several studies have reported a reduction in GABA function, availability,

and activity in autism. Researchers have found that activity in the caudate

nucleus, a critical part of circuits that link the prefrontal cortex of the

brain, is reduced in boys with autism. The caudate nucleus is part of the

striatum. 96% of the neurons in the striatum are spiny neurons, which are

GABAergic.

Other sources of support for a GABAergic mechanism in the etiology of autism

spectrum disordersb are diverse. One source comes from a case in which an

individual with a rare autosomal recessive disorder that prevented the proper

synthesis of GABA was diagnosed with ASD, seizures, and severe mental

retardation. Another source of support comes from a study in which PET scans

have revealed a 60% reduction in the binding of the benzodiazepine radioligand

iomazenil in the cerebellum of a person with autism, with a deletion of the

maternal allele of chromosome 15q11-13.

b. GABA Receptor Abnormalities

1) GABA Receptors Generally

Receptors for GABA are divided into two main classes: GABAA receptors, which

are members of the ligand-gated ion channel superfamily, and GABAB metabotropic

receptors which belong to G protein-linked receptors. Both types of GABA

receptors are abundant in the brain, and found in almost all types of neurons

and many populations of glial cells.

GABAA receptors are the most ubiquitous neurotransmitter receptor in the

mammalian nervous system. In young differentiating neurons, most important

effects of GABA are mediated through GABAA receptors. During development, GABAA

receptors, along with AMPA / Kainite glutamate receptors, mediate CA2+ dependent

signal transduction pathways capable of influencing many brain developmental

processes, including proliferation, synaptogenesis, and circuit formation. GABAB

receptor mediated effects, which can cause hyperpolarization and reduce CA2+,

appear in later phases of tissue genesis and seem to balance GABAA signalling.

The GABAA receptor is the target for steroids, such as THP (or

allopregnanolone), which reduce anxiety. GABAA receptors normally calm activity

in the brain. As such, they are the targets for most sedative, tranquilizing

drugs. However, at the onset of puberty, the interaction of THP with the GABAA

receptors reverses course in the part of the brain that regulates emotion.

Instead of instilling calmness, THP reduced the inhibition produced by these

GABAA receptors, increasing brain activity to produce a state of increased

anxiety.

2) GABA Receptors and Sensation

In several electrophysiological investigations GABAA receptor antagonists were

applied to the spinal cord resulting in an enhanced response to light touch.

This supports a role for GABA and GABAA receptors in somatosensation. Previous

findings likewise implicate GABAA receptors in tonic inhibition of low threshold

afferent inputs to the spinal cord and also suggest high threshold

thermoreceptive inputs to the spinal cord are tonically inhibited to a lesser

extent.

3) GABA Receptors and Autism

A decrease in GABA receptor binding has been shown in autism. An imbalance in

the availability of GABA receptor subunits may alter receptor activity and hence

change the activity of the brain's major inhibitory neurotransmitter. As a

consequence, the threshold for developing seizures, a frequent comorbidity with

autism, might be reduced among other effects.

Histological, biochemical, and molecular approaches have demonstrated altered

levels and distribution of GABA and GABA receptors in peripheral blood and

plasma, as well as in the brain, including decreased GABAA receptors and

benzodiazepine binding sites in the hippocampal formation of autistic

individuals.

Duke researchers have identified one gene called GABRA4, which controls the

GABAA4 receptor, as being associated with autism risk. Interaction with a second

gene known as GABRB1 (controlling the B1 receptors) appeared to drive this risk.

In addition, mutations have been reported in multiple GABA receptor genes in

families with epilepsy.

As discussed in more detail below, mice deficient in the GABRB3 gene exhibit a

wide assortment of neurochemical, electrophysiological, and behavioral

abnormalities, many overlapping traits typically observed in autism, including

hypersensitivity to thermal and tactile stimuli, hyperactivity, motor

stereotypies, poor motor coordination, and lengthened cycles of rest and

activity. Concordance amongst GABA receptor B3 subunit mutation, cleft palate,

autism, and FAS strongly implies that the GABAA receptor B3 subunit may be a

common mediator for these disorders.

Human chromosome 15q11-13 is associated with the neurodevelopmental disorders

autism, Angelman syndrome, and Prader-Willi syndrome. A number of genes that

have been associated with autism have been identified within this region

including a cluster of GABA receptor subunit genes, GABRB3, GABRA5 and GABRG3.

Numerous studies have demonstrated the importance of the GABAergic system in

neurodevelopment; therefore, the presence of a group of GABA receptor genes

within this locus is intriguing.

c. Knockout Mice

1) GABRB3 Null Mice

The GABRB3 knockout mice are probably the best mouse model for autism. The

GABRB3 receptor is widely expressed during the late embryonic to early postnatal

period of brain development, and its deletion in mice disrupts GABA related

pharmacology and electrophysiology and produces behaviors reminiscent of autism.

A deficiency in the B3 subunit during this critical period would be expected to

negatively impact the temporal ordering of neurogenesis and synaptogenesis.

Homozygous disruption of GABRB3 in mice reduces GABAA receptor binding by half,

and GABA activated chloride current from sensory neurons is reduced by 80%;

similar, lesser effects are observed in heterozygotes. As a result, GABRB3

knockout mice have epileptiform EEG containing high amplitude slow and sharp

waves, and develop overt seizures as they mature; they also have learning and

memory deficits reminiscent of autism spectrum disorders.

a) Sensory Responsiveness

One of the earliest traits noted in GABRB3 null mice was they were

hyperresponsive to being handled or exposed to other sensory stimuli, which

usually culminated in the expression of hyperactive behavior and stereotypical

circling. GABRB3 null mice also display enhanced responsiveness to low frequency

thermal stimuli. In addition, GABRB3 null mice exhibit enhanced responsiveness

to innocuous tactile stimuli compared to wild type mice.

It has been suggested that some of the motor manifestations of the

hyperexcitability / hyperresponsivity seen in the GABRB3 null mice may be due to

the ineffectiveness of spinal presynaptic inhibition resulting from the decline

in GABAA receptor expression on the terminals of primary afferents. Likewise, if

GABAergic inhibition were compromised in the dorsal root ganglion of autistic

individuals one would expect these individuals to be hyperresponsive to sensory

input.

Pharmacological studies in sensory neurons taken from both GABRB3 null mice and

control litter mates further indicate there is little or no compensation for the

loss of the B3 subunit by the other B subunits. GABAA receptors on the terminals

of sensory afferents in the dorsal and ventral horn of the spinal cord are

expected to provide presynaptic inhibition. And, the majority of postsynaptic

GABAA receptors in the spinal cord express mRNA for the B3 subunit.

B) Seizures / EEG Abnormalities

Virtually all GABRB3 mice experience some form of recurring spontaneous seizure

stating at about 10 weeks of age and becoming more frequent as they age.

Seizures were usually followed by a period of behavioral quiescence. EEG

measurements performed on GABRB3 null mice revealed an evolving electrocortical

phenomenon in which young GABRB3 null mice display relatively normal EEG traces

that become markedly abnormal as the mice age. This may be explained by the fact

that the number of GABAergic synapses gradually decrease as the mice age.

A variety of anti-epilepsy drugs have been administered to GABRB3 null mice,

with ethosuxomide being the most potent in lessening seizures and normalizing

EEG abnormalities. Ethosuxomide is generally used for the control of seizures

and works by inhibiting T-type calcium channels involved in synchronization of

thalamocortical circuitry.

c) Sleep Patterns

GABRB3 null mice exhibit significantly less REM sleep time compared to wild

type mice. This finding is in line with studies supporting the crucial role for

GABAergic transmission in the regulation of REM sleep, thereby implicating the

B3 subunit of the GABAA receptor in the regulation of the cortical expression of

sleep states.

2) GABRB2 Null Mice

Mice lacking GABRB2 subunits exhibit epileptiform seizures and behavioral

symptoms of GABRB1 knockout mice indicating the necessity of both subunits for

normal GABRB signalling.

3) uPAR Mice

Disruption of GABAergic interneuron development during the embryonic and early

postnatal periods can have profound neurological and behavioral consequences.

Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an

important molecular cue that may guide the movement of interneurons from their

birthplace in the ganglionic eminences (GE) to their final resting place in the

neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in

pallidal and subpallidal tissues is associated with a reduction in the number of

cells migrating out of GE explants. The uPAR knockout mouse provides a unique

opportunity to study the effects of interneuron disruption in vivo. uPAR-/- mice

have reduced HGF/SF bioactivity in the GE during the period of interneuron

development and a concomitant 50% reduction in the number of GABAergic

interneurons seeding frontal and parietal regions of the cerebral cortex.

Behaviorally, these mice display an increased susceptibility to seizures,

heightened anxiety, and diminished social interaction. This suggests that

disruption of GABAergic interneuron development may represent a common point of

convergence underlying the etiologies of many of these developmental disorders.

d. GABA and the Cerebellum

The cerebellum is the brain region that has been most consistently implicated

in autism. In particular, the large GABAergic Purkinje cells have been shown in

abnormally reduced numbers.

1) The Structures of the Cerebellum

a) The Deep Cerebellar Nuclei

The deep nuclei of the cerebellum ( " DCN " ) act as the main centers of

communication, and the four different nuclei of the cerebellum (dentate,

interpositus, fastigial, and vestibular) receive and send information to

specific parts of the brain. In addition, these nuclei receive both inhibitory

and excitatory signals from other parts of the brain which in turn affect the

nuclei's outgoing signals.

B) The Cerebellar Cortex

The cerebellar cortex consists of molecular, Purkinje cell, and granular

layers. Each layer contains distinct types of neurons. Among the five types of

main neurons, four of them, Purkinje, stellate, basket, and Golgi cells, release

GABA as a neurotransmitter.

This outermost layer of the cerebellar cortex contains two types of inhibitory

interneurons: the stellate and basket cells. Stellate cells are small cells

lying in the outer two thirds of the molecular layer; basket cells are located

in the inner third in close proximity to the Purkinje cell layer. The basket and

stellate cells receive excitatory inputs from the parallel fibers of the granule

cells and the climbing fibers and direct their output by inhibiting Purkinje

cells and granule cells. The inner layer of the cortex is the granule cell

layer. Cerebellar granule cells are the smallest and most numerous neurons in

the mammalian brain and have a simple morphology with an average of only four

short dendrites, each dendrite receiving a single excitatory mossy fiber input.

Each granule cells also receives input from one or two Golgi cells, the major

granule layer interneuron.

The granule cells are excitatory interneurons and their axons form the parallel

fibers that project to Purkinje cells but also form synapse contacts with cells

in the molecular layer. Cerebellar granule cells receive inputs from the mossy

fibers coming from the vestibular nuclei. The Golgi cells are inhibitory

interneurons of the cerebellum that have their cell bodies located mostly in the

upper half of the granule layer. Golgi cells receive inputs from, and project

their inhibitory output to granule cells, continuing a negative feedback

circuit.

Purkinje cells are arranged in a single layer between the molecular and

granular layers. This layer contains the dendritic arbors of Purkinje neurons

and parallel fiber tracts from the granule cells. Each Purkinje cell receives

excitatory input from 100,000 to 200,000 parallel fibers of the granule cells

(this is a crucial point of interaction in autism). Purkinje cells, the pivotal

neurons of the cerebellar cortex, receive excitatory inputs from climbing

fibers, granule cell axons, and parallel fibers, and send inhibitory output to

the deep cerebellar nucleus. The other GABAergic neurons, stellate, basket, and

Golgi cells, negatively regulate above the major stream of cortical circuits at

the Purkinje cell dendrites, cell bodies and granule cell dendrites,

respectively.

In striking contrast to the 100,000-plus inputs from parallel fibers, each

Purkinje cell receives input from exactly one climbing fiber axon, which

originates in the inferior olive. The climbing fiber `climbs' the dendrites of

the Purkinje cell and wraps them forming a series of very strong synapses, with

each presynaptic spike triggering a postsynaptic spike. Climbing fibers may

serve a special function other than ordinary signal transmission - an

instructive signal that regulates the strength of parallel fiber / Purkinje cell

synapses.

2) The Functions of the Cerebellum

The cerebellum is an extremely important element of the human brain that was

until recently largely misunderstood. Recent evidence that the cerebellum is

involved in perception and cognition challenges the prevailing view that its

primary function is fine motor control. A new hypothesis is that the lateral

cerebellum is not activated by the control of movement per se, but performs a

general support function for the nervous system as a whole.

The cerebellum is right in the middle of the flow of sensory information from

the peripheral nervous system. The cerebellum receives input from possibly all

sensory systems and projects to many cerebral cortical areas. Anatomical studies

show that there are substantial anterograde and retrograde connections in humans

between the hypothalamic nuclei and all four cerebellar nuclei (and cerebellar

cortex), as well as with thalamic neural groups.

The cerebellum is strongly engaged during the acquisition and discrimination of

sensory information, monitoring and adjusting the acquisition of this sensory

data. Scientists have been examining cerebellar involvement in tactile and

auditory processing and have accumulated evidence in both cases that the

cerebellum plays a central role in regulating the sensory data on which

computation in the somatosensory and auditory systems depends. The cerebellum

has significant involvement in the volume and intensity of sensory information

that is passed onto the processing centers of the brain.

To understand the computations performed by the input layers of the cortical

structures, it is essential to determine the relationship between sensory evoked

synaptic input and the resulting patterns of output spikes. In the cerebellum,

granule cells constitute the input layer, translating mossy fiber signals into

parallel fiber input to Purkinje cells, which act at the output layer for the

cerebellar cortex. Granule cells exhibit a low ongoing fire rate, due in part to

dampening of excitability by a tonic inhibitory conductance mediated by GABAA

receptors.

Sensory stimulation produces bursts of mossy fiber excitatory post synaptic

current (EPSCs) that sum to trigger bursts of spikes. Notably, spontaneous

(non-clustered) mossy fiber inputs trigger spikes only when tonic inhibition is

reduced (as may occur after nitric oxide release or with changes in steroid

levels). During blocking of tonic inhibition, single mossy fiber EPSCs are on

occasion capable of triggering action potentials, with spontaneous firing rate

increasing by an order of magnitude and driving granule cell output. This is a

critical requirement if the network is to remain sensitive to low levels of

afferent activity.

Findings that bursts of action potentials in granule cells are triggered by

clustered sensory evoked mossy fiber EPSCs complement and enhance existing

theories of cerebellar function that propose that the granule cell layer is a

low noise sparse coding system. This burst to burst sequence ensures that

granule cells reliably relay sensory evoked mossy fiber signals, whereas events

not associated with sensory stimulation are filtered out. Bursting thus further

enhances the signal to noise ratio for transfer of sensory information in an

input layer exhibiting low firing rates.

Bursts in granule cells have special relevance for the cerebellar network, as

the downstream synapses made onto Purkinje cells show frequency dependent

facilitation of transmitter release and glutamate receptor activation,

suggesting that granule cell bursting will be nonlinearly amplified at the next

synaptic relay. This will enhance postsynaptic activation of the Purkinje cells

through both ascending branch and parallel fiber synapses, with the duration of

the burst offering a relatively broad window for postsynaptic coincidence

detection. Because induction of synaptic plasticity at these synapses is also

highly frequency dependent, granule cell bursting may provide a substrate for

the storage of sensory representation.

The input layer of the cerebellum balances exquisite sensitivity with a high

signal to noise ratio. Granule cell bursts are optimally suited to trigger

glutamate receptor activation and plasticity at parallel fiber synapses,

providing a link between input representation and memory storage in the

cerebellum.

3) Disruptions in Cerebellar Balance Generally

Any disruption in the inhibitory-excitatory balance of inputs to either

Purkinje cells or DCN cells potentially can have profound consequences to the

output of the DCN and presumably affects functionality of the

nucleo-olivocerebellar system and/or the dentatorubrothalamic tract projecting

back to cerebral cortical area. Some DCN cells are GABAergic and it has been

demonstrated that these inhibitory neurons project back to the inferior olive to

modulate its activity. Since firing of inferior olivary neurons to synchronize

via coupled electrical synapses, disruption in the GABAergic feedback of the DCN

could potentially interfere with the ability of the inferior olivary neurons to

generate coherent rhythmic outputs thus slowing overall cognitive processing

speed. Alternations within this circuit due to possible miswiring, hyper

innervation of climbing fibers to its Purkinje cell and/or DCN targets, or

innervation of fewer targets due to cell loss, would also have the potential of

disrupting the modulatory effects of cerebellar function.

4) Cerebellar Abnormalities and Autism

Research in recent years has started to confirm that abnormalities in

cerebellum size and shape are regularly seen in persons with autism. Dr.

Corchesne is one of numerous researchers that has demonstrated in autism a

consistent reduction of cerebellar size which is due to Purkinje neuron loss in

the cerebellar hemispheres and sometimes the cerebellar vermis. For instance,

Temple Grandin is probably the most well known autistic person. MRI scans of

Temple's brain indicate her cerebellum is 20% smaller than normal.

a) Cerebellar Defects Generally

Particularly implicated in deficits of long-range connectivity and coordination

of cognitive functions is the cerebellum, which, in autistics, often shows

arrested development of the cerebellar vermis and hemispheres and reductions in

numbers of cerebellar Purkinje cells. In autism, cerebellar activation has been

shown to be abnormally low during a task of selective attention and abnormally

high during a simple motor task. Such a reduction would release the DCN from

inhibition, producing abnormally strong physical connectivity and potentially

abnormally weak computational connectivity along the cerebello-thalamo-cortical

circuit.

Cerebellar connections with the limbic system and with the cerebral cortex have

been posited as mediating abnormal activity that underlies the motor and sensory

abnormalities, language difficulties, socio-emotional difficulties, and

disordered cognitive processing seen in autism. Cerebellar pathology could lead

to abnormal activity in cerebello-limbic and cerebello-thalamo-cortical

pathways, which in turn could be expressed as autistic behavior. This altered

pattern of cortical excitation may produce aberrant activity-dependent

patterning and may thus be related to findings of abnormal individual

variability in cortical maps for motor function and face processing and to

abnormal overgrowth in frontal lobes.

A recent study showed that when allowed to explore freely an open area

containing novel objects, children with autism spent less time exploring the

novel information than normal children, and that the more abnormal their

exploration behavior, the smaller the cerebellar vermis. Rats with cerebellar

lesions show deficits in long term habituation of the acoustic startle response

and increased spontaneous motor activity and perseverative behavior.

B) Purkinje Cells

Most studies that have looked at the cerebella of autistic people have shown

reduced Purkinje cell numbers. This reduction in Purkinje cells presumably leads

to disinhibition of the cerebellar deep nuclei and consequent overexcitation of

the thalamus and cerebral cortex. In autism, it is more likely that cerebellar

abnormalities may better correlate with functional and high order behavioral

alterations rather than classical motor disturbances.

In one study of four brains from autistic patients, researchers found reduced

Purkinje cell density. In a study by Ritvo, all autistic cases showed a reduced

number of Purkinje cells in the cerebellar vermis and hemisphere. Other

researchers found a 24% decrease in mean Purkinje cell size in autistic brains.

Still other research groups have reported decreased number of cerebellar

Purkinje cells without significant gliosis and features of cortical dysgenesis.

These findings suggest a largely prenatal origin of autism.

Some researchers have postulated that because the cerebellar laminar pattern is

not disturbed in autism, it is likely that Purkinje cells were generated,

completed their migration to the Purkinje cell layer, and then subsequently

died. If the Purkinje cells died just after they established their position in

the Purkinje cell layer, before the elaboration of much of their dendritic tree,

then it is likely that there would be a loss of interneurons, especially

stellate cells, unable to make stabilizing synapses with their major targets.

But because there is no difference in the density of GABAergic interneurons in

the cerebellar molecular layer in autism, at least in the most affected area of

reported Purkinje cell loss, this infers that basket and stellate cells were

able to make stabilizing synaptic contacts prior to the Purkinje cell death.

Therefore, from the results of Whitney's research, the timing of Purkinje cell

loss in autism is most likely not before 32 weeks of gestational age but may

extend into early postnatal development since completion of migration of the

external granule layer in humans is not complete until about 18-20 months.

I think it is possible that something else is going on. Something that should

be considered is that the reduction in number of Purkinje cells is a result of

an evolutionary adaptation that simply resulted in fewer Purkinje cells, and

that cells were not created that died during development. As discussed in later

Sections, there may be evolutionary reasons for this.

c) Deep Cerebellar Nuclei

Age dependent changes were observed in the deep cerebellar nuclei such that

brains from young autistic individuals exhibited unusually large neurons in all

four deep cerebellar nuclei with older individuals (older than 22) showing

unusually small and pale neurons with qualitative observations of diminished

neuronal numbers in the fastigial, globose and emboliform nuclei.

d) Receptors

Purcell compared the gene expression in the cerebella of autistic patients with

neurotypicals. It was discovered that there was a higher expression of a

transporter for excitatory effective amino acids and for an AMPA sensitive

non-NMDA glutamate receptor. The density of these receptors has been proved

however to be decreased.

4. GAD (Glutamic Acid Decarboxylase) Deficiency

Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the

decarboxylation of glutamate to GABA and CO2. It exists in two forms, GAD65 and

GAD67. Its levels have been shown to be abnormally low in bipolar disorder,

schizophrenia, and autism.

Abnormalities in both GAD subtypes have been reported in autism, implying a

deficit in GABA. Lower GABA levels could reduce the threshold for developing

seizures which are often associated with autism.Autistic parietal and cerebellar

cortices are reported to have an approximately 50% reduction in protein levels

of the enzymes that synthesize GABA, GAD65 and GAD67.

Fatemi found reduced levels of both GAD 65 and GAD 67 in autistic parietal and

cerebellar cortices. Another group of researchers recently examined brain levels

of GAD in five autistic and eight controls. They found that this enzyme was

reduced by 48-61% in parietal and cerebellar areas of brains of individuals with

autism compared to controls. In another study of seven young adult autistics

aged 19-30, the mean GAD65 values in the cerebellum were reduced by 51% and

GAD67 reduced by 61%, both highly significant. Another researcher found a 40%

decrease in GAD67 mRNA in Purkinje cells in autistic cases relative to controls

and this difference was found whether there was a decrease in Purkinje cell

count or not.

Mice deficient in GAD65 mRNA and protein demonstrate conditional fear behavior,

spontaneous seizure, lowered threshold for seizure inducing drugs, and increased

anxiety-like behavior. Reduction of GAD levels in mice lacking GAD65 is

associated with epilepsy and a block in the development of neocortical

processing of binocular visual input. Mice lacking the GAD65 gene have defective

cortical plasticity that can be corrected with a GABA agonist. GAD67 null mice

develop cleft palate and die the day of birth with no discernible defects in the

brain structures.

5. Imbalance Due to Improper Synaptogenesis of Excitatory / Inhibitory

Synapses

a. Neuroligins / Neurexin

Synapse assembly requires anterograde and retrograde trans-synaptic signaling,

as well as signaling within each presynaptic and postsynaptic component.

Signaling between beta-neurexin and neuroligin may orchestrate coordinated

presynaptic and postsynaptic development. Neuroligins are a family of

postsynaptic transmembrane proteins, which have been shown to induce

differentiation of presynaptic structures when expressed in non-neuronal cells.

One possibility is that this induction could occur through interaction of

neuroligin with the presynaptic transmembrane protein beta-neurexin, but a

requirement for this interaction in synaptogenesis has been difficult to

demonstrate in vivo because the complexity of the genes involved has taxed

traditional knock-out strategies.

Recent work provides strong evidence that beta-neurexin-neuroligin signaling

indeed promotes synapse formation. Different neurexin/neuroligin combinations

appear to participate in specifying whether new synapses are assembled into

excitatory or inhibitory synapses. The basic findings are that over expression

of neuroligins or beta-neurexin induces presynaptic or postsynaptic

differentiation, respectively, of both excitatory and inhibitory synaptic

components in hippocampal neurons, while down regulating the level of neuroligin

expression by RNA interference inhibited the differentiation and maturation of

excitatory and inhibitory synaptic contacts. Over expression of the postsynaptic

density protein PSD95, which is known to increase excitatory synapse formation,

recruits neuroligin to clusters of excitatory synaptic proteins, indicating that

the trans-synaptic signaling that occurs during synapse formation and the

establishment of a matrix of postsynaptic density proteins are mechanistically

linked. Electrophysiological recordings further suggest that neuroligins and

PSD95 are important for establishment of excitatory versus inhibitory synapses.

Synapses are weakened and lost in neurodegenerative diseases such as

Alzheimer's and Parkinson's disease. Synapse function goes awry in psychiatric

disorders such as schizophrenia, depression and autism. PSD-95 may be involved

in this. Like the steel girders in a building, it acts as a scaffold around

which other components are assembled. The more PSD-95 molecules present, the

bigger and stronger the synapse. Mice genetically altered to have less PSD-95

experienced learning and memory problems. Phosphorylation is critical for PSD-95

to do its job in supporting synapses. Adding a phosphate group to a single amino

acid allows PSD-95 to promote synapse size and strength.

b. Neuroligins / Neurexin in Autism

Researchers led by Scheiffele have reported that decreased levels of

neuroligin, known to occur in abnormally low concentrations in some people with

autism, reduced the number of synapses between rat neurons. The researchers say

reduced neuroligin levels could contribute to the communication failures between

brain cells that result in autism. In an experiment where researchers suppressed

the gene that produces neuroligins, the most striking difference is that there

is about a 60 percent reduction in the number of spines compared to the number

in control cells. When cells lack neuroligins, the balance between excitation

and inhibition is perturbed and then the cell cannot normally function in the

circuit anymore.

Based on Fragile X research, researchers are currently exploring the

possibility that alterations in synapse development and signaling may underlie

some forms of autism. This perspective has been bolstered by the identification

of function-altering mutations in some neuroligin genes in a small subset of

autistic people. Genetic abnormalities, including point mutations and

chromosomal rearrangements, in loci corresponding to the genes for the synaptic

proteins neuroligin and PSD95, are apparently associated with autism. Recently,

mutations in neuroligin 3 and 4 have been identified in some autistic boys.

Early in 2008, researchers at UI identified deletions in a gene called neurexin

1 which caused the two cases of autism in one family. Genes with the most

compelling evidence of causing autism appear to be components of a specific kind

of neuronal connection, or synapse, called the glutamate synapse. The gene

neurexin 1 was the fourth of these genes to be identified, and it is a

scientifically interesting mutation because it wasn't found in either of the

parents, who do not have autism. Instead, the mutation is a germline mosaic -

meaning the deletion occurred only in the father's sperm cells. As a result, the

father did not have autism, but his two children, both daughters, inherited from

him a chromosome that was missing a small piece of DNA that contained neurexin

1. The daughters now have autism. Because of this missing DNA, certain proteins

cannot form that normally contribute to glutamate synapses and, by extension,

normal development.

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