Project Summary

Fabrice Jean-Raymond Ango, Ph.D. (Young Investigator 2005) of Cold Spring Harbor Laboratory, plans to study the role of the protein neurofascin in the regulation of the brain’s GABAergic circuit, a system which may be involved in the impairment of working memory in schizophrenia. Research shows that alterations in the GABAergic circuit are restricted to a subset of interneurons, including chandelier and basket neurons, containing the calcium binding protein parvalbuim. Chandelier and basket interneurons innervate the axon initial segment (AIS) and soma of pyramidal neurons, and therefore provide control over pyramidal neuron output. However, the cellular and molecular mechanisms underlying GABAergic synaptic innervation at AIS and their alteration in schizophrenia remain unknown. Dr. Ango’s laboratory has discovered that neurofascin, a cell adhesion molecule that is member of the L1 immunoglobulin superfamily, is a key molecule directing GABAergic innervation at AIS of Purkinje neurons in the cerebellum. Dr. Ango hypothesizes that neurofascin subcellular localization is a general mechanism that also specifies GABAergic innervation at AIS of pyramidal neurons in neocortex, including the prefrontal cortex. The laboratory will test this hypothesis using mutant mice in which the subcellular localization of neurofascin is disrupted, and in other transgenic mice. These studies should provide a new approach for the development of treatments to prevent/ameliorate mental disorders, such as schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\Molecular

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