Regular - spiking cells in the presubiculum are hyperexcitable in a rat model of 2 Temporal Lobe Epilepsy

30 Temporal Lobe Epilepsy (TLE) is the most common form of adult epilepsy, characterized 31 by recurrent seizures originating in the temporal lobes. Here, we examine TLE-related changes 32 in the presubiculum (PrS), a less-studied parahippocampal structure that both receives inputs 33 from and projects to regions affected by TLE. We assessed the state of PrS neurons in TLE 34 electrophysiologically to determine which of the previously identified cell types were rendered 35 hyperexcitable in epileptic rats and whether their intrinsic and/or synaptic properties were 36 altered. Cell types were characterized based on action potential discharge profiles followed by 37 unsupervised hierarchical clustering. PrS neurons in epileptic animals could be divided into three 38 major groups comprising of regular-spiking (RS), irregular-spiking (IR) and fast-adapting (FA) 39 cells. RS cells, the predominant cell type encountered in PrS were the only cells that were 40 hyperexcitable in TLE. These neurons were previously identified as sending long-range axonal 41 projections to neighboring structures including medial entorhinal area (MEA), and alterations in 42 intrinsic properties increased their propensity for sustained firing of action potentials. Frequency 43 and amplitude of both spontaneous excitatory and inhibitory synaptic events were reduced. 44 Further analysis of non-action potential-dependent miniature currents (in TTX) indicated that 45 reduction in excitatory drive to these neurons was mediated by decreased activity of excitatory 46 neurons that synapse with RS cells concomitant with reduced activity of inhibitory neurons. 47 Alterations in physiological properties of PrS neurons and their ensuing hyperexcitability could 48 entrain parahippocampal structures downstream of PrS, including the MEA, contributing to 49 temporal lobe epileptogenesis. 50