Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury

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Abstract Post-traumatic epilepsy (PTE) can result from combat-related traumatic brain injury (TBI), a well-documented phenomenon that has caused substantial neurologic disease in Veterans, most recently in relation to conflicts in the Middle East (>350,000 cases of combat-related TBI since 2000). Unfortunately, current treatments for PTE are of limited efficacy, and thus many Veterans with PTE do not have effective seizure control. PTE often manifests as a form of temporal lobe epilepsy, which involves cellular and functional circuit alterations in the hippocampal region of the brain. In the healthy hippocampus, dentate granule cells (DGCs) form a principal cell layer that prevent hyperexcitability through their low firing frequency and relatively hyperpolarized resting membrane potentials. Additionally, the dentate gyrus is a region of ongoing neurogenesis, in which new DGCs are generated throughout adult life and integrate into the existing circuitry, in a process critical to learning and memory. TBI and epilepsy involve the aberrant maturation and integration of adult-born DGCs in the hippocampus, which is thought to disrupt hippocampal function and increase brain excitability leading to seizures. In this region, parvalbumin-positive (PV+) inhibitory basket interneurons not only mediate feed-forward inhibition, but release the neurotransmitter GABA onto immature granule cells and neuroblasts, which modulates circuit integration of these cells as they mature in the hippocampus. Although these interneurons are preserved in many animal models of epilepsy, PV+ basket cells undergo numerous functional and network changes, including reduced excitatory input, increased output failure, and presynaptic calcium channel dysfunction. Prior hypotheses have examined the potential direct contribution of PV+ cell dysfunction to hippocampal hyperexcitability after TBI. In this proposal, I hypothesize that dysfunction of PV+ basket cells after TBI contributes indirectly to hyperexcitability, by driving aberrant maturation and integration of adult-born DGCs. I will investigate how TBI impacts PV+ basket cell function at the cellular and network level, how this dysfunction influences development and integration of adult-born DGCs, and whether changes in PV-cell specific microcircuit structure and function drive whole animal seizure susceptibility following TBI. This proposal will use transgenic mice to selectively target the PV+ basket cell population for expression of calcium indicators, excitatory channelrhodopsins, or specific synthetic receptors to measure PV-cell specific network activity after TBI, as well as the functional outputs of these cells. I will also combine these techniques with retrovirus-mediated labeling of adult-born DGCs, to determine whether changes in post-TBI PV+ basket cell function alter the maturation, integration, or circuit dynamics of adult-born DGCs after TBI. Finally, I will manipulate activity of the PV+ basket cells in vivo to assess their role in neuronal circuit rewiring after TBI, and modulate their activity after TBI in hopes of reducing seizure susceptibility. The knowledge gathered from this study will help guide future work that will refine our understanding of interneuron dysfunction for post-TBI injured Veterans using clinical data, which might one day be able to prevent the development of PTE.