Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits

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Abstract

Neocortical interactions with the dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson's disease, and Huntington's disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of the molecular mechanisms that control generation of prefrontal cortex–striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin-8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in the medial prefrontal cortex and in striatal medium spiny neurons forming the direct or indirect pathways. Developmental analysis of quantitative real-time polymerase chain reaction and western blot data show that Cdh8 expression peaks in the prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron microscopy shows that Cdh8 is concentrated at excitatory synapses in the dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together, our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. J. Comp. Neurol. 523:75–92, 2015. © 2014 Wiley Periodicals, Inc.

Using combinations of single-molecule FISH, tract tracing, and immuno-EM, the authors show that Cadherin-8 (Cdh8) is enriched in corticostriatal neurons of prefrontal cortex and in both direct- and indirect-pathway striatal medium spiny neurons, where it localizes to synapses. Functional analysis shows that Cdh8 is involved in dendrite arborization and self-avoidance. Thus, Cdh8 delineates developing corticostriatal projections and plays a role in morphofunctional development of this circuit.

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