Neuronal circuits maintain a delicate balance of excitatory drive and inhibitory regulation to execute high order functions, such as learning and memory, and maintain network stability which is severely compromised in temporal lobe epilepsy (TLE). The hippocampal dentate gyrus (DG) acts as a functional gate into the hippocampal trisynaptic circuit and plays a key role in learning and memory. Formation of memories is believed to be coded by activity of a distinct collection of neurons which represent a memory or experience known as an engram. Sparse activity in dentate granule cells (GCs) has been shown to be involved in engram formation; however, the circuit mechanism that underlie formation of these neuronal activity patterns are not fully understood. Recent studies have found that a sparse subtype of dentate projection neurons, semilunar granule cell (SGC) are preferentially recruited in engrams. SGCs differ from GCs in their wide dendritic arbors, molecular layer axon collaterals and persistent firing and have been proposed to support feedback inhibition of GCs. However, circuit connectivity and functional effects of SGCs are not known. The objective of this dissertation is to better understand SGC’s role in the dentate circuit, their role in DG circuit processing as well as alterations to their synaptic inputs epilepsy. I hypothesized that SGCs refine GC engrams by driving a subset of GCs in the engram and supporting feedback inhibition of surrounding “non-engram” GCs. My findings indicate that SGCs have more frequent excitatory inputs, with higher inputs from the medial entorhinal cortex (known to contain spatial information). I report that SGCs are reliably recruited as part of a spatial engram due to its heightened excitability compared to GCs. GCs and SGCs adapt differently in response to pilocarpine induced epilepsy and epileptic mice are unable to use a spatial search strategy in our special behavior paradigm. These studies provide novel fundamental insights into dentate circuit function and memory processing.

Neuroimmune signals within the brain have a dual role in modulating neurophysiology both at baseline and in response to injury and infection. The primary focus of existing literature is on how inflammatory cascades affect network excitability following injury or in disease states. In these studies, we focus on the innate immune receptor, Toll-Like Receptor 4 (TLR4), and identify its novel neurophysiological roles in regulating hippocampal dentate excitatory and inhibitory networks under basal conditions and after fluid percussion injury (FPI) which impact working memory and behavior. Using CLI-095, a specific TLR4 antagonist, and a combination of local field potential recordings in the presence of glial metabolic inhibitors and whole cell voltage clamp recordings, we demonstrate a constitutive role of TLR4 in the uninjured dentate gyrus. This basal TLR4 signaling is absent in the presence of glial metabolic inhibitors and selectively modulates granule cell GABAergic inhibitory currents. In uninjured mice, blocking TLR4 decreased input driven evoked inhibitory post synaptic currents (eIPSCs) and impaired both working memory function in a Morris Water Maze task and spatial pattern separation in a Novel Object Location Task. In contrast, glial signaling is not required for TLR4 modulation of dentate excitability after brain injury. Specifically, neuronal expression of TLR4 enhances excitatory calcium permeable AMPA currents and reduces inhibitory GABA currents one week after brain injury. FPI resulted in early hilar somatostatin (SST) neuron loss, decreased eIPSC amplitude, and impaired working memory and spatial pattern separation at one week. Consistent with our finding that TLR4 is expressed on SST, but not parvalbumin interneurons, cell-type specific deletion of TLR4 in SST neurons identified that TLR4 expression in SST neurons as crucial for the injury-induced decrease in dentate eIPSC and behavioral deficits. These results indicate a differential role for cell-type specific TLR4 signaling in modulating of synaptic currents in granule cells from control and FPI mice. These studies demonstrate a novel role of TLR4 in modulating inhibitory synapses at baseline as well as after injury and provides promising therapeutic potential whereby acute targeting of TLR4 signaling after brain injury may limit post-injury increases in dentate excitability by augmenting synaptic inhibition.