GABAergic transmission regulates neuronal excitability, integration, plasticity, and has been implicated in the generation and entrainment of oscillatory population activity patterns in mammalian brain during perception, learning, and cognition. A salient feature of GABAergic innervation is the targeting of specific classes of GABAergic synapses to restricted subcellular compartments of principal neurons (dendrite, soma, and axon initial segment-AIS). Such spatial organization of inhibitory synapses contributes to the temporal precision of GABAergic regulation, yet the underlying mechanism is almost entirely unknown. We hypothesize that subcellular localization and function of L1 family immunoglobulin cell adhesion molecules in principal neurons and glia cells constitutes a set of common molecular code, which directs the subcellular organization of distinct classes of GABAergic synapses along principal neurons through both permissive and repulsive signaling. Combining GABAergic cell type specific promoters, bacterial artificial chromosome transgenic mice, and high resolution imaging, we have developed both in vivo and in vitro methods to visualize and genetically manipulate specific classes of interneurons and to test our hypothesis. In particular, we will examine the role of neurofascin and CHL1 in targeting GABAergic synapses to soma-AIS and dendrites of principal neurons both in cerebellum and neocortex. Aberrant GABAergic function is correlated with states of mental illness. """"""""Subtle"""""""" defects in cortical GABAergic connectivity, including subcellular synapse targeting, have been implicated in devastating neurological and psychiatric disorders such as epilepsy and schizophrenia. Mutations in L1 and CHL1 genes have also been linked to mental retardation, aphasia, and Tourette syndrome. The establishment of a causal link between L1CAMs and construction of GABAergic circuits should provide a new perspective for understanding the molecular pathology of these mental illnesses and for treatment strategies.
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