Project 3-Regulation of Cortical GABAergic Connectivity by NCAM

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Neural cell adhesion molecule NCAM (11q23) performs vital roles in learning and memory by regulating guidance of CMS axons. NCAM merits study as a schizophrenia vulnerability gene, as NCAM polymorphisms are associated with neurocognitive impairment in a schizophrenia population (CATIE). Moreover, a soluble NCAM fragment consisting of the entire extracellular region (NCAM-EC) is overexpressed in schizophrenic brain, and is released from normal neurons by proteolytic cleavage (ectodomain shedding) by a metalloprotease with properties of an ADAM (a disintegrin and metalloprotease). Excess NCAM shedding in the prefrontal cortex (RFC) was modeled in NCAM-EC transgenic mice, which revealed a striking decrease in synapses of GABAergic interneurons, including basket cells that regulate pyramidal cell output and synchrony. NCAM-EC mice display behavioral abnormalities associated with neurotransmission defects, including hyperlocomotion, stereotypies, decreased sensory gating and fear conditioning. It is hypothesized that NCAM regulates the excitatory/inhibitory balance between basket interneurons and pyramidal cells in the RFC, and that dysregulation of NCAM by excessive shedding perturbs synaptic connectivity, thus altering cortical circuitry and synchrony of pyramidal cell groups important for neurocognition. GABAergic function may be compromised in schizophrenia, but it is not known if GABAergic dysfunction reflects altered development of cortical circuitry. It will be determined if there are developmentally regulated changes in dendritic/axonal arborization and synaptogenesis of GABAergic interneurons and pyramidal neurons in normal RFC,and whether NCAM dysregulation interferes with development in NCAM-EC and null mutant mice. NCAM shedding will be assessed during development in post-mortem human brain and from individuals with schizophrenia. Cortical neuron cultures will be exploited to identify the ADAM protease(s) responsible for normal NCAM shedding, to localize the NCAM cleavage site, and to ascertain the role of NCAM shedding on neuronal process outgrowth and branching. Finally, behavioral testing in mice will assess whether NCAM-EC overexpression impairs executive functions such as working memory, decreases gamma oscillatory activity, and alters sensitivity to GABA agonists in anxiety- like behavior and sensorimotor gating. This work will assist other center investigators in understanding development of GABAergic interneurons from early differentiation (Project 4), migration (Projects 4 and 5), and establishment of connections (this project) and will characterize a molecular substrate for abnormal neurocognitive functions in patients who are at risk or in early stages of schizophrenia (Projects 1 and 3).These studies will illuminate a mechanism whereby NCAM contributes to GABAergic cortical circuitry relevant to neurocognitive function, and will explore NCAM as a pathophysiological target for schizophrenia vulnerability.