Without Dopamine, Neurons Continue to Fire Normally

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Without Dopamine, Neurons Continue to Fire Normally

Research update from Medical Institute

http://www.hhmi.org//news/palmiter2.html

Researchers are learning whether normal neuron behavior depends on the

ability to produce an essential neurotransmitter. Recent studies in

living mice indicate that dopamine-producing neurons are capable of

triggering nerve impulses even when they are deprived of dopamine.

According to the study's senior author, Medical Institute

researcher Palmiter, at the University of Washington, Seattle,

these kinds of basic questions are important to ask because

dopamine-producing neurons are affected in a number of disorders,

including Parkinson's disease, attention deficit hyperactivity disorder,

schizophrenia, and Tourette's syndrome. Their activity is also

implicated in most forms of drug abuse.

“Past experiments had involved making dopamine-deficient mice by killing

the neurons, but obviously you can’t study the properties of a neuron

once it is dead. In our mouse, though, the neurons seem perfectly

healthy, but they are in essence ‘firing blanks.’”

D. Palmiter

The results of the experiments, performed by Siobhan in

Palmiter's lab, are published in the September 7, 2004, issue of the

Proceedings of the National Academy of Sciences.

Dopamine is a neurotransmitter, a specialized chemical messenger that

plays a specific role in the brain. When neurons release

neurotransmitters in bursts, they trigger nerve impulses in neighboring

neurons. The finding that dopamine-deprived neurons continue to fire

normally, including in bursts, even in the absence of dopamine suggests

that neuronal inputs from other neurons play a major role in influencing

the firing pattern of dopamine neurons.

“Among the unanswered questions in neurobiology is whether a neuron is

controlled by some sort of feedback mechanism that regulates how often

it fires,” Palmiter said. “We were asking a relatively simple question:

Can a neuron fire properly in the absence of its own neurotransmitter?”

To address that question, Palmiter and his colleagues turned to a mouse

that they had genetically engineered to lack an enzyme known as tyrosine

hydroxylase, which converts the amino acid tyrosine to L-DOPA, which is

then converted into dopamine. “Past experiments had involved making

dopamine-deficient mice by killing the neurons, but obviously you can't

study the properties of a neuron once it is dead,” said Palmiter. “In

our mouse, though, the neurons seem perfectly healthy, but they are in

essence `firing blanks.' They don't have any dopamine in their synaptic

vesicles that can be released to activate other neurons.”

Mice lacking dopamine manifest symptoms of a severe form of Parkinson's

disease - they move very little and fail to eat adequately, said

Palmiter. However, when the animals are injected with L-DOPA, thereby

bypassing the need for the enzyme that was missing in their bodies, the

animals behave normally for a few hours until the dopamine produced in

their brains is degraded.

The scientists recorded the behavior of the neurons in awake, behaving

animals, which meant that the experimental conditions were more natural

than some previous experiments, which used anesthetized mice. When

measured the activity of the neurons after the mice had

received L-DOPA, she was surprised to find that even though this

treatment stimulated the animals to eat and move about, their

dopaminergic neurons were substantially inhibited. “We realized this was

part of the feedback system that regulates these neurons. Lacking

dopamine, the neurons had become hypersensitive to the neurotransmitter.

So, when dopamine is restored, they become overly excited and respond by

inhibiting the dopaminergic neurons, to achieve a normal level of

reactivity,” said Palmiter. Thus, these dopamine neurons fire normally

in the absence of dopamine but are sensitive to feedback inhibition when

dopamine signaling is restored.

Two possible feedback systems might be regulating the dopaminergic

neurons. The “short-loop” pathway involves feedback control by receptors

on the dopamine neurons themselves. The “long-loop” pathway involves

dopamine-responsive brain circuitry. According to Palmiter, both

pathways likely contribute to the feedback control, but the long-loop

pathway is likely to be more critical.

An important observation emerged when the researchers subjected the

dopamine-deficient mice to anesthesia. They found that the firing rate

of the dopamine neurons is greatly reduced in the dopamine-depleted

animals, whereas is relatively unaffected in control mice. These

findings underscore the importance of measuring the activity of dopamine

neurons in awake animals, Palmiter said. Furthermore, they help explain

why earlier studies with anesthetized mice led to the erroneous

conclusion that the dopamine neurons were inactive in the absence of

dopamine.

According to Palmiter, further studies will aim to discover the neural

inputs that regulate the activity of dopamine neurons. At the moment,

the simplest idea is that dopamine-producing neurons receive lots of

inputs from other circuitry in the brain, and those circuits may be

unaffected by the absence of dopamine,” said Palmiter. “Those neurons

don't know that there isn't any dopamine, and they may continue to

influence the firing pattern of the dopaminergic neurons.”