Cell-type specific GABA signaling is required for newborn neuron incorporation

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DESCRIPTION (provided by applicant): Traumatic brain injury is arguably the most significant neurological problem affecting our Veterans, leading to such devastating problems as refractory epilepsy and debilitating cognitive deficits. While the initial injury is important in determining eventual outcome, many of these problems do not manifest themselves until several years later. These delayed sequelae are thought to be due to pathological plasticity, including cell death, axonal sprouting, and changes in protein expression. Recently, the study of adult neurogenesis has emerged as a promising approach to provide both insight into the mechanisms of and potential treatment for brain injury. Transplanted embryonic interneurons have been used to ameliorate symptoms in a number of animal models of neurological disorders, and endogenous neurogenesis is robustly enhanced following brain injury. However, many of these newborn neurons are morphologically and functionally very abnormal, and may actually contribute to pathological changes following brain injury. A key hole in our understanding of pathological postinjury plasticity is an understanding o the signals directing how newborn neurons become incorporated into normal adult circuits. GABAA Receptors (GABARs) are particularly crucial morphogenic molecules directing neuronal proliferation, migration and synaptic integration. GABARs are heteropentameric protein complexes, typically containing 2 1, 2 2 and either a single 3 or 4 subunit protein. The identity o the 1 subunit isoform (11-6) is a key determinant of GABAR function, capable of producing profound differences in the kinetic properties and pharmacological sensitivity of GABARs. While 11 containing GABARs are the primary mediators of synaptic inhibition in mature neurons, there is a progression from 14 to 12,3 to 11 predominant GABAergic signaling that is an extraordinarily consistent finding in both embryonic neurons, as well as newborn neurons of the adult. A similar program of expression has also frequently encountered following already established neurons following adult brain injury. While GABA generally evokes inhibitory responses, activation of GABARs during this transitional period produces depolarizing responses, allowing GABA to serve as a powerful morphogen. Perturbations of depolarizing GABA cause aberrant neuronal maturation that depends critically on the cell type (interneuron vs principal cell) and developmental stage in question. While it is clear that GABAR function depends critically on the subunit combination, the significance of specific GABAR expression patterns during neuronal incorporation remain very poorly understood. In order to elucidate the role of specific GABAR subunit combinations, we will characterize the time-dependent evolution of GABAR subunit isoform expression, as well as the biophysical properties of the predominant GABARs being expressed. Finally acute brain slice recording with post-hoc morphological and immunocytochemical analysis will be used to correlate the changes in GABAergic signaling as a function of cell-type and maturational state. The overarching hypothesis is that the expression of specific GABAR subunit isoforms with unique biophysical properties are spatially and temporally locked with neuronal maturation in a cell-type specific manner to effectively mediate the evolving roles of GABAergic signaling required for incorporation into functional circuits. Our long term goal is to understand how this system becomes pathologically recapitulated following brain injury, and use this information to develop specific pharmacological treatments to prevent and treat the chronic neurological sequelae of brain injury. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is arguably the most significant neurological problem affecting our Veterans, leading to such devastating problems as refractory epilepsy and debilitating cognitive deficits. Brain injury often leads to delayed sequelae due to pathological plasticity, that in many ways resemble a perverse recapitulation of development. GABA, the primary inhibitory neurotransmitter in the adult brain, serves a dual role that involves excitatory responses to direc these maturational processes. This period of excitatory GABA is mediated by an unusual cohort of GABA receptors that are normally expressed only at low levels in healthy, adult brain. In this project, we will seek to elucidate the cell-type specific changes in GABAergic signaling that direct neuronal incorporation, with a long term goal of using this information to develop subtype- specific GABA receptor ligands to prevent and treat brain injury induced neurological diseases.