Bidirectional Tyrosine Kinase Signaling

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DESCRIPTION (provided by applicant): Our project is centered on studies of the brain that will help us better understand how neural networks that often go haywire in psychiatric disorders are built during development. Normal functioning of the cerebral cortex depends critically on the precise balance of excitatory neurons and inhibitory neurons, which together control the flow of information and synchronization of neural networks necessary for higher order brain activity. Disturbances in forebrain GABAergic inhibitory interneurons can affect the delicate balance between excitation and inhibition, leading to hyperexcitability and neuropsychiatric diseases such as epilepsy, autism, other intellectual disabilities, schizophrenia, and mood disorders. While these conditions are distinct from each other, they typically have in common disturbances in the number/distribution/function of forebrain interneurons. This suggests related mechanisms are in play to establish and maintain the homeostatic balance of excitatory and inhibitory signals necessary for normal brain activity and that disruption of interneuron function leads to imbalances with pathological consequences. Great progress has been made in recent years by the identification genes that contribute to psychiatric disorders in humans, including the highly conserved neuronal EphB2 receptor tyrosine kinase. Knockout mice are particularly attractive animal models to analyze how mutation of such genes in the rodent affects interneuron development and leads to psychiatric-type behaviors. Despite these advancements our knowledge of the molecular mechanisms that regulate interneuron migration and integration into the cortical network remains rudimentary. In our ongoing studies of the EphB receptors and their transmembrane ephrin-B ligands, we have generated new conditional brain-specific mutant mice and find they present with seizures and abnormal hyperexcitable autistic-like behaviors that are associated with defective interneuron populations in the cortex and hippocampus. Our new data allows us to hypothesize that Eph/ephrin-B cell-to-cell signaling is an essential component of interneurons required for normal excitatory/inhibitory (E/I) balance. To further build this new link between Eph/ephrin-B signaling, interneuron development, and E/I balance, we will determine how specific loss of ephrin-B's within the GABAergic cell type affects interneuron migration into the developing forebrain and axonal/dendritic/synaptic morphology in the developed brain. Electrophysiological and behavioral studies will assess how loss of ephrin-B in inhibitory neurons affects E/I balance and leads to abnormal autistic-like behaviors. To complement the analysis of GABAergic specific conditional knockouts, intracellular ephrin-B mutants will be studied to determine the role of reverse signaling in interneurons. Through the described experiments we will gain a better understanding of how the ephrin-B proteins participate in regulating cortical E/I balance and function to prevent formation of abnormal psychiatric-type behaviors.