Abstracts

Rationale: Temporal lobe epilepsy is one of the most common types of epilepsy in adults and causes pervasive memory impairments which significantly impact patients’ quality of life. In pilocarpine-treated epileptic mice, we have recently found desynchronized interneuron firing between the CA1 and dentate gyrus regions of the hippocampus (HPC). The medial entorhinal cortex (MEC) is the upstream region sending and receiving direct spatial inputs into and from HPC. However, it remains unclear whether synchronization deficits in HPC reflect impaired inputs from MEC and when these deficits emerge following epileptogenesis. Cognitive processes require precise communication between circuits, suggesting that altered timing between HPC and MEC may contribute to epilepsy-associated cognitive deficits. We have recently found progressive spatial memory deficits in epileptic mice that emerge between 3 and 8 weeks after pilocarpine. In this project, we tested whether MEC-HPC synchronization is disrupted in epileptic mice before and after progressive memory deficits emerge.

Methods: We performed simultaneous in vivo electrophysiology with 512-channel silicon probes in HPC and MEC of head-fixed epileptic and control mice running in virtual reality. We recorded at two timepoints (3 and 8 weeks after pilocarpine) to capture synchronization changes during the progression of memory impairments.

Results: To break our findings into three major parts: Within HPC, we found epileptic mice show theta power and coherence deficits early in disease progression. We also found inhibitory cells in CA1 and DG are less phased locked to CA1 theta oscillations at both early and late time points. Within MEC, epileptic mice show decreased theta coherence between layer MEC layer2 (MECII) and 3 (MECIII) only at the later time point but not early. In terms of single unit phase locking, we found disrupted excitatory and inhibitory neuron phase locking of MECII cells to local MECII theta. Between MEC and HPC, we found misaligned communication in epileptic mice, especially at the later timepoint. Theta coherence between MEC and HPC was significantly decreased at 8 wk but not 3 wk post pilocarpine injection. Interestingly, MECII inhibitory cells show disrupted phase locking to CA1 theta oscillation at both earlier and later time points.

Conclusions: Together, these data reveal three main points. First, both HPC and MEC are desynchronized in the chronic phase of pilocarpine-induced epilepsy with altered theta power, theta coherence, and phase locking of single units. Second, HPC desynchronization emerges earlier than MEC, matching the earlier timeline of seizure onset. Third, we identified progressive impairments in the synchrony within MEC and between the MEC-HPC circuit throughout the development of epilepsy, which matches the timeline of progressive memory deficits. These findings suggest that MEC desynchronization likely contributes to poor spatial memory and spatial coding found in epileptic mice.

Funding: R01NS116357 (TS), CURE Taking Flight Award (TS), AES Junior Investigator Award (TS), AES Predoctoral Award (SF)