Antipsychotic drug and cortical development

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DESCRIPTION (provided by applicant): Despite unknown, long-term risks for their children, many pregnant women must take antipsychotic drugs (APDs) because interruption of pharmacotherapy would jeopardize the women's ability to carry on their daily lives and to care for their children. APDs modulate serotonergic and/or dopaminergic synaptic transmission. Serotonin and dopamine also regulate dendritic development which, in turn, is a key determinant of neuronal connectivity and function. Thus, limited periods of APD exposure during development may cause long-lasting, behaviorally significant changes in cortical circuitry. Our preliminary data support this hypothesis. APD-treated mice appear to be impaired in behavioral tests that assess the function of several cortical areas. In these areas, cortical pyramidal cell dendrites normally develop by a combination of constructive and regressive events and early APD exposure can accelerate, retard or inhibit these events. Aim 1 investigates the normal ontogenetic progression of changes in dendritic form. Aim 2 examines the long-term effects of APDs on dendritic architecture and effects of APDs on the ontogeny of dendritic form. Aim 3 investigates the long-term effects of early APD exposure on behavior and cognition, and also examines potential normalizing influences of behavioral training on APD-induced alterations of dendritic form. In Aim 4, ablation of individual monoamine receptors by null mutations and measurements of the effects of experimental treatments on stress responses are used to investigate some potential mechanisms of APD-induced effects. Our results help assess the potential long-term risks of APD use by pregnant women. Our method can be applied to assess the risks of maternal use of other therapeutic- and illegal drugs, and can be used to study the biology of various neurodevelopmental disorders. Thus, our results can aid in the design of new therapies that improve clinical outcomes.