New Thinking on Neurodevelopment

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http://www.ehponline.org/members/2006/114-2/focus.html

from New Thinking on Neurodevelopment

Not Immune to Harm

Exposure to a neurotoxicant may not be the only way to disrupt the

natural growth of the brain. Scientists are now looking at the subtle

physiological effects of immunotoxicants and infectious agents on

biological events during development.

It turns out that mothers who experience an infection during pregnancy

are at a greater risk of having a child with a neurodevelopmental

disorder such as autism or schizophrenia. For example, prenatal exposure

to the rubella virus is associated with neuromotor and behavioral

abnormalities in childhood and an increased risk of schizophrenia

spectrum disorders in adulthood, according to an article in the March

2001 issue of Biological Psychiatry. Rubella has also been linked to

autism: some 8-13% of children born during the 1964 rubella pandemic

developed the disorder, according to a report in the March 1967 Journal

of Pediatrics. The same study also noted a connection between the

rubella virus and mental retardation.

Some epidemiologic studies have found an increased risk of schizophrenia

among the children of women who were exposed to the influenza virus

during the second trimester of pregnancy, according to a report in the

February 2002 Current Opinion in Neurobiology. In the August 2004

Archives of General Psychiatry, Ezra Susser, head of epidemiology at

Columbia University's Mailman School of Public Health, and his

colleagues reported that the risk of the mental disorder was increased

sevenfold if the schizophrenic patient's mother had influenza during her

first trimester of pregnancy. A prospective birth cohort study in the

April 2001 Schizophrenia Bulletin found that second trimester exposure

to the diphtheria bacterium also significantly increased the risk of

schizophrenia.

How might infectious agents cause these disorders? According to

Gilmore, a professor of psychiatry at the University of North Carolina

at Chapel Hill, maternal infections during pregnancy can alter the

development of fetal neurons in the cerebral cortex of rats. The

mechanism is far from clear, but signaling molecules in the mother's

immune system, called cytokines, have been implicated. Speaking at the

XXII International Neurotoxicology Conference, Gilmore described in

vitro experiments showing that elevated levels of certain

cytokines--interleukin-1?, interleukin-6 and tumor necrosis factor-alpha

(TNF-alpha )--reduce the survival of cortical neurons and decrease the

complexity of neuronal dendrites in the cerebral cortex. " I believe that

the weight of the data to date indicates [that the maternal immune

response] can have harmful effects, " says Gilmore.

Inflammatory responses in the mother may not be the only route to

modifying the fetal brain. The University of California, , Center

for Children's Environmental Health and Disease Prevention is conducting

a large study of autistic children in California called CHARGE

(Childhood Autism Risks from Genetics and the Environment), which

suggests that the child's immune system may also be involved. According

to Pessah, the study principal investigator, children with autism appear

to have a unique immune system. " Autistic children have a significant

reduction in plasma immunoglobulins and a skewed profile of plasma

cytokines compared to other children, " he says. " We think that an immune

system dysfunction may be one of the etiological cores of autism. "

He continues, " We know that many of the things that kids are exposed to

these days are immunotoxicants. . . . We have evidence that ethylmercury

and thimerosal alter the signaling properties of antigen-presenting

cells, known as dendritic cells, at nanomolar levels. " Since each

dendritic cell can activate 250 T cells, any dysregulation will be

magnified, he says. " Add to that a genetic abnormality in processing

immune information, and there could be a problem. "

Such problems might extend to the central nervous system. The brains of

individuals who have a neurodevelopmental disorder also show evidence of

inflammation. In the January 2005 issue of the ls of Neurology,

Pardo, an assistant professor of neurology and pathology at the

s Hopkins University School of Medicine, and his colleagues report

finding high levels of inflammatory cytokines (interleukin-6,

interleukin-8, and interferon-gamma ) in the cerebrospinal fluid of

autistic patients. Glial cells, which serve as the brain's innate immune

system, are the primary sources of cytokines in the central nervous

system. So it may not be surprising that Pardo's team also discovered

that glia are activated--showing both morphological and physiological

changes--in postmortem brains of autistic patients.

The recognition that the immune system is involved in neurodevelopmental

disorders is changing people's perceptions of these conditions.

" Historically, scientists have focused on the role of neurons in all

kinds of neurological diseases, " Pardo says, " but they have generally

been ignoring the [glia]. " He adds, " In autism, it could be that the

[glia] are responding to some external insult, such as an infection, an

intrauterine injury, or a neurotoxicant. "

According to Pardo, it's still not clear whether the neuroimmune

responses associated with autism contribute to the dysfunction of the

brain or whether they are secondary reactions to some neural

abnormality. " Gilmore's work [showing that cytokines can be harmful

to brain cells] is quite interesting and important, " he says. " However,

in vitro studies may produce results that don't reflect what occurs

under in vivo conditions. Cytokines like TNF-alpha may be beneficial for

some neurobiological functions at low concentrations, but may be

extremely neurotoxic at high concentrations. "