Jean M. LauderDepartment of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7090.
Neurotransmitters appear to have evolved to their highly specialized roles in the vertebrate nervous system from primary cellular functions in lower organisms, including regulation of cell proliferation, differentiation, migration and morphogenesis, by receptor-mediated mechanisms. Neurotransmitters also play important growth-regulatory roles during vertebrate neural development. These evolutionarily conserved functions make the developing nervous system especially vulnerable to environmental neurotoxins designed to target neurotransmitter receptors.
GABA, the main inhibitory neurotransmitter in the vertebrate brain, acts as a trophic (positive) growth regulatory signal for developing neurons in many brain regions, including embryonic brainstem serotonin (5-HT) neurons. The trophic actions of GABA are mediated primarily by GABAA receptors. Therefore, the developing serotonergic nervous system is a potentially vulnerable target for organochlorine pesticides that act as potent GABAA receptor antagonists. We have found that exposure of pregnant rats to lindane, dieldrin or bicuculline (a classical GABAA antagonist) reduces expression of multiple GABAA receptor subunits in fetal brainstem, and decreases [35S]TBPS binding, indicating that they can interfere with fetal development of the GABAregic system.
In embryonic brainstem cultures GABA acts as a trophic signal for developing 5-HT neurons, promoting their growth and survival. These effects are blocked by bicuculline indicating that they are mediated by GABAA receptors. Dieldrin strongly inhibits growth and survival of 5-HT neurons. These effects appear to be irreversible since they cannot be eliminated by GABA. Surprisingly, both dieldrin and bicuculline promote development of GABA neurons, suggesting that GABA itself may be part of a negative feedback loop regulating development of its own neurons. This unexpected finding also raises the possibility that prenatal exposure to organochlorine pesticides like dieldrin could produce opposite effects on GABAergic and serotonergic systems in vivo, perhaps altering the balance between inhibitory and excitatory neurotransmission in the developing brain.
We have begun to investigate consequences of prenatal exposure to organochlorine pesticides (dieldrin, lindane) or bicuculline for development of the serotonergic system (5-HT neurons and receptors). Preliminary results indicate that prenatal exposure to bicuculline causes a significant reduction in 5-HT during the postnatal period [postnatal days (PND) 5-25]. However, by early adulthood (around PND 60) 5-HT reaches control levels. Similar to 5-HT, 5-HT1A receptors are reduced at early postnatal ages, but appear to rebound thereafter, exceeding controls by the late postnatal period. Studies are currently underway to determine whether prenatal exposure to dieldrin or lindane may cause more potent and permanent effects on development of the serotonergic nervous system.
In the context of autism, it is important to determine whether environmental insults to developing neurotransmitter systems may compromise brain development in genetically susceptible populations. In future studies, we plan to utilize emerging mouse models for autism to determine whether developmental exposure to organochlorine pesticides may exacerbate phenotypes caused by targeted gene mutations.
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