Project 3

Regulation of Cortical GABAergic Connectivity by NCAM

Description

Prinicipal Investigator: Patricia Maness, PhD

We will evaluate the hypothesis that interference with NCAM function in developing PFC, either by overexpression of NCAM-EC or NCAM deletion, perturbs connectivity of GABAergic basket interneurons and pyramidal cells important for cortical circuits that might underlie such executive functions as working memory.  Mechanistically, NCAM-EC in developing brain may act as a dominant negative inhibitor of full length NCAM, which is co-expressed with NCAM-EC both in transgenic mice and in schizophrenic brain.

Specific Aim 1.  To investigate the hypothesis that NCAM promotes axonal/dendritic elaboration of GABAergic basket interneurons and pyramidal cells in the mouse prefrontal cortex in vivo, and that NCAM-EC interferes with their development.

Specific Aim 2.  To determine whether ADAM10 and/or ADAM17 are reponsible for ERK-regulated NCAM cleavage in cortical neurons in culture, to localize the NCAM cleavage site, and to identify the effects of NCAM shedding on branching and outgrowth of neuronal processes.

Specific Aim 3.  To determine whether NCAM-EC transgenic mice have impairments in working memory and altered sensitivity to GABA agonists in anxiety-like behavior and sensorimotor gating.