Molecular control of prefrontal cortical circuitry in autism

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) comprise a range of neurodevelopmental abnormalities in cognitive abilities and behaviors associated with dysfunctional circuitry between the prefrontal cortex (PFC) and the neostriatum. Behavioral abnormalities emerge early after birth and are thought to reflect defects in the fine- tuning and plasticity of developing functional synaptic connectivity. We have observed that mRNA encoding cadherin-8 (Cdh8)-a type II, synaptically-localized classic cadherin-is highly enriched in PFC and dorsal striatum during early postnatal development. Moreover, the timing, anatomical distribution, and axon targeting function of Cdh8 suggest strongly that Cdh8 may be crucial for the development and plasticity of PFC->striatal circuitry. This is significant because several recent studies have linked Cdh8 genetically to susceptibility to ASDs. Thus, we hypothesize that cognitive ASD-like phenotypes reflect impaired synaptic development of PFC->striatal direct- and/or indirect-pathway circuitry due to deficient Cdh8-dependent molecular control over these pathways. We will test this hypothesis by combining mouse genetics, anatomy, and electrophysiology. The vertical integration across these objectives (spanning molecules, synapses and circuits) will provide novel insight into molecular control of brain pathways implicated in cognitive deficits associated with ASDs. This is important, because corticostriatal circuit defects are central to a number of aberrant behaviors associated with autism and anxiety disorders, but there is surprisingly little known about the normal development and plasticity of such circuits.