Synaptic integration of newborn neurons after traumatic brain injury

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) often causes long-term deficits in learning and memory (8). The hippocampus, a critical brain structure for memory (9, 10), generates an increased number of newborn neurons after TBI (11- 14). These new neurons may contribute to cognitive recovery (15-18). However, neurons born in pathologic conditions often form maladaptive connections that would impact their utility in terms of memory formation and could lead to disorders such as seizures (19, 20). The mechanisms underlying post-traumatic neurogenesis are not clear, although a variety of neurotransmitter systems are known to modulate neurogenesis, most notably GABAa and NMDA receptor signaling (21-24). Importantly, both of these receptors are directly targeted by sedatives used in severely head injured patients during immediate post-injury care. For instance, the proliferation, differentiatio and maturation of newborn neurons are regulated by GABAergic signaling (21, 22), and the survival of newborn cells is regulated by NMDA receptors (21, 23, 24). As such, it is conceivable that sedatives, such as diazepam and ketamine, which modulate these receptors, might differentially affect the post-traumatic neurogenic response, altering the proliferation, survival and integration of newborn cells, which could affect functional recovery. The long-term objectives of this research are to determine whether newborn neurons generated after TBI have altered functional properties, and to determine whether exposure to specific sedatives after injury alters this process. Our hypothesis is that cells born after TBI have an accelerated development and synaptic integration, that this involves changes in GABAergic signaling, and that both the proliferation and integration of newborn neurons will be differentially affected by sedatives. Specific Aim 1 will begin addressing this by determining changes in the proliferation, migration, dendritic morphology and electrophysiological properties of hippocampal neurons born after TBI, including an analysis of GABAergic receptor activity. Specific Aim 2 will determine whether exposure to mechanistically distinct sedatives alters these properties of neurogenesis [and also determine whether sedative-mediated changes in post-traumatic neurogenesis are associated with changes in cognitive function and/or seizure susceptibility.] Our goal is to gain a better understanding of the function of the neurons generated after injury, as well as gain an understanding of how neurogenesis after injury is affected by sedative medications. The findings from this work will lead to translational studies with the goal of optimizing post-TBI hospital care and improving functional recovery after brain injury.