Project Summary: Neurological disorders such as epilepsy and memory loss develop several years after traumatic brain injury (TBI) and are a major source of physical disability and economic burden. The delay between the initial trauma and eventual disability results from progressive neuropathology that could be limited by early interventions. However, mechanisms by which TBI impacts memory and seizure susceptibility are not fully understood. The hippocampal dentate gyrus, a circuit critical for memory processing, a key regulator of information transfer from entorhinal cortex to hippocampus, and a niche region for adult neurogenesis, is a focus of neuronal damage and increased excitability after TBI. Although adult born granule cells (abGCs) are implicated in memory processing, the contribution of abGCs to dentate spikes which represent entorhinal cortex to dentate information flow and support memory consolidation is not known and how injury-induced changes in neurogenesis affect memory processing is not fully understood. Unexpectedly, we find that suppressing injury-induced increase in neurogenesis reduces dentate excitability one week after TBI, during the same period when posttraumatic increase the innate immune receptor, toll-like receptor 4 (TLR4) augments dentate excitability. TLR4 is known to suppress neurogenesis in naïve animals and paradoxically increase neurogenesis in stroke. While the molecular mechanisms by which TLR4 regulates excitability and neurogenesis are unknown, recent findings that TLR4 enhances the endopeptidase, matrix metalloproteinase- 9 (MMP-9), a critical player in synaptic plasticity and neurogenesis provides a promising molecular link between trauma, TLR4 and aberrant network plasticity. In an integrative approach spanning molecular to cellular to network function, we propose that early increase in neurogenesis and excitability after TBI disrupt dentate regulation of cortico-hippocampal throughput and contribute deficits in memory processing by TLR4- dependent persistent elevation of MMP-9 activity. Using the fluid percussion injury model in mice and current in vivo and ex vivo electro- and optophysiological techniques, Aim 1 will determine the role of TLR4 signaling in altered development, maturation and circuit integration of abGCs born after injury. Aim 2 will test if altered DG excitability and neurogenesis after TBI compromise oscillatory coupling between dentate and hippocampus which can be prevented by blocking TLR4 early after injury. Finally, Aim 3 will use a combination of histological, biochemical, physiological, and behavioral assays to test if aberrant TLR4 signaling after TBI results in persistent increase in MMP-9 which can be targeted to limit aberrant neurogenesis, deficits in oscillatory coupling and memory deficits after TBI. Such preventive strategies will greatly improve the quality of life of patients after TBI and address the NINDS mission of decreasing the long-term health care burden posed by post-traumatic neurological diseases.

Narrative: There are over 2 million annual cases of traumatic brain injury contributing to debilitating sequelae such as epilepsy and cognitive disability emphasizing the need to identify mechanisms and therapies. Studies proposed here will test a novel molecular pathway involving immune receptor mediated activation of a specific endopeptidase as a mechanisms for abnormal birth, integration, and function of neurons in the dentate gyrus after brain injury. The experiments will test whether circuit changes after trauma impair brain rhythms involved in memory processing and examine the therapeutic potential of posttraumatic inhibition of the endopeptidase in preventing epilepsy and memory deficits after brain injury.