Ohio State University, the

Molecular Mechanisms Underlying Cortical Interneuron Synaptic Specificity - Project Summary/abstract Cortical Inhibitory Gabaergic Interneurons (ins), Which Develop Intricate Local Circuits, Critically Regulate Higher- Order Brain Functions by Balancing and Shaping Neuronal Activity. Consistent With Its Indispensable Role in Normal Brain Functions, Malformation/malfunction of the Inhibitory System Is Implicated in a Wide Array of Brain Disorders Such as Schizophrenia, Autism, and Epilepsy. Despite Their Importance, the Molecular Mechanisms Underlying the Wiring of in Local Circuits Remain Largely Unknown. Cortical Ins Comprise Diverse Cell Types That Are Defined by Morphology, Physiology, and Gene Expression. Notably, Different in Subtypes Also Show Distinct Synaptic Specificity at Laminar/cellular as Well as Subcellular Levels. Although Subtype-specific Synaptic Connectivity Is Considered a Critical Property of Ins to Ensure Functional Diversity of the Inhibitory System, the Molecular Mechanisms Underlying in Synaptic Specificity Remains Poorly Understood. the Objective of This Proposal Is to Determine the Molecular Mechanisms by Which in Subtypes Establish Layer/cell Type- and Subcellular Domain-specific Synapses. to Achieve This Goal, We Will Perform a Series of Experiments Using Chandelier Cells (CHCS), Which Exclusively Innervate Axon Initial Segments (AISS) of Layer-specific Pyramidal Neurons (PNS). the CHC Is Known to Critically Regulate PN Spike Generation and Has Been Implicated in Schizophrenia and Epilepsy. Besides Their Functional Significance, the Stereotypy of Their Synaptic Organization Make CHCS an Attractive Model to Study the Molecular Mechanisms for in Synaptic Specificity. Our Preliminary Data Has Shown That: (1) IGSF11 Proteins That Are Known to Bind With Each Other Are Expressed in Both CHCS and Layer-specific Target PNS, (2) GLDN Proteins That Are Known to Bind to Ais-enriched Proteins, NF186, Are Preferentially Expressed in CHCS, (3) IGSF11 in CHCS Plays an Essential Role in Their Presynaptic Development, (4) GLDN and NF186 Appear to Play a Role in Initiating CHC Synapses, and (5) IGSF11 That Is Free From the GLDN-NF186 System Appears Not to Induce CHC Synapses. Based on Our Findings, We Propose to Test the Hypothesis That the Layer-specific Synaptogenic Action and the Subcellular Domain-specific Recognition Mediated Through IGSF11 Homophilic Interactions and GLDN-NF186 Interactions, Respectively, Cooperatively Determine CHC Synaptic Specificity. We Will Pursue the Following Specific Aims to Test Our Hypothesis. in Aim 1, We Will Determine the Role of the IGSF11 Homophilic Interaction Between Pre- and Postsynaptic Neurons in Layer-specific Synapse Formation by CHCS. in Aim 2, We Will Determine the Role of GLDN and NF186 in CHC Synapse Formation on Aiss. in Aim 3, We Will Determine the Regulatory Role of NF186/GLDN in Gating IGSF11 Signaling to Induce CHC Presynaptic Boutons at Aiss. Upon Completion of This Study, We Will Gain Not Only Important Insights Into Molecular Mechanisms for in Wiring But Also a Clue to Developing Therapeutic Strategies to Functionally Repair Disordered/damaged Brains.