Project Summary/Abstract: Impaired inhibitory circuits are thought to underlie hyperactive neuronal networks in neurodevelopmental disorders. Aberrant synaptic wiring and hypofunction of parvalbumin (PV) expressing interneurons has been shown to contribute to impaired inhibition in several neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and epilepsy. Mechanisms that control PV synaptic wiring are still under investigation, as relatively few have been identified. Ephs and ephrins are a class of receptor tyrosine kinases (RTK) and their ligands, which are known to be involved in a diverse array of neuronal developmental processes including cell migration, axon guidance, and synaptogenesis. EphB overexpression in PV interneurons has been shown to negatively regulate perisomatic synapse formation. The effect was possibly due to contact-dependent repulsion mediated by Eph/ephrin signaling as EphB/ephrin-B interactions can mediate cellular repulsion. Astrocytes express ephrin-B1, the ligand for EphB receptor, and may affect inhibitory synapse development and maintenance through its interactions with neuronal Eph receptors. Indeed, recent work in our lab has shown that astrocytic ephrin-B1 negatively regulates excitatory synapse formation but positively regulates inhibitory synapse formation and inhibition of excitatory neurons (Ex) in the CA1 hippocampus of developing, but not adult mice. However, the mechanism by which astrocytic ephrin-B1 controls perisomatic inhibitory synapse development and function has not been described. Preliminary data show a specific reduction in PV-positive perisomatic synapses following deletion of astrocytic ephrin-B1. The focus of this proposal is to (1) determine if perisomatic inhibition is altered following developmental deletion of astrocytic ephrin-B1 due to changes specifically in PV- evoked responses or if other perisomatic targeting interneurons, such as cholecystokinin (CCK) interneurons are also affected and (2) to determine if astrocytic ephrin-B1 positively regulates perisomatic inhibitory synapse formation through removal of EphB receptors from PV boutons, preventing repulsion between Ex and PV cells. I propose to use multidisciplinary approaches, including immunohistochemistry, whole cell electrophysiology, optogenetics, live cell imaging, and biochemistry to determine the perisomatic inhibitory innervation that is affected by developmental deletion and overexpression of astrocytic ephrin-B1, and to investigate the underlying mechanism. The proposed research will describe novel astrocyte mediated mechanisms promoting perisomatic inhibitory synapse formation, which could be utilized as a therapeutic target for treating neurodevelopmental disorders.