Project Summary/Abstract Toll-Like Receptor 4 (TLR4) is an innate immune receptor that is enhanced after brain injury and is implicated in modulating excitability in the hippocampal dentate gyrus. We find that suppressing TLR4 after brain injury reduces seizure susceptibility and memory deficits however has opposite effects in controls. In pilot studies, TLR4 signaling increases synaptic inhibition to dentate granule cells in controls while reducing it after TBI, indicating that inhibition may be central to the differential TLR4 effects in control and injured brain. TLR4 is localized in dentate hilar neurons and co-localizes with somatostatin, not parvalbumin interneurons. Since TLR4 effects on inhibition correlate with dentate excitability and memory outcomes, I propose that cell type specific and injury-state dependent TLR4 modulation of GABAergic synapses regulate dentate excitability and memory processing. Using single/dual patch clamp recordings, cell-specific patterned optogenetic neuronal activation and pharmacology in a rodent model of brain injury, I will resolve TLR4 regulation of synaptic inputs from SOM+ and PV+ neurons to granule cells in control and injured animals. Mice with cell-specific deletion of TLR4 will be subject to brain injury and probed for TLR4 regulation of network function using a novel in-vitro temporal pattern separation assay and behavioral pattern separation tasks. The study will advance basic knowledge on immune regulation of excitability and memory processing and identify potential targets to limit post-traumatic changes in neuronal activity.
