Authors :
Presenting Author: Susie Yu Feng, BS – Icahn School of Medicine of Mount Sinai
Lucia Page-Harley, MS – Icahn School of Medicine of Mount Sinai; Keziah Diego, BS – Icahn School of Medicine of Mount Sinai; Zhe Dong, PhD – Icahn School of Medicine of Mount Sinai; Sophia Lamsifer, BS – Icahn School of Medicine of Mount Sinai; Zoé Christenson Wick, PhD – Icahn School of Medicine of Mount Sinai; Paul Philipsberg, MS – -, Icahn School of Medicine of Mount Sinai; Lauren Vetere, BS – Icahn School of Medicine of Mount Sinai; Ivan Soler, BS – Icahn School of Medicine of Mount Sinai; Zach Pennington, PhD – Icahn School of Medicine of Mount Sinai; Julia Schnipper, n/a – Northwestern University; Albert Jurkowski, n/a – Hunter College; Denise Cai, PhD – Icahn School of Medicine of Mount Sinai; Tristan Shuman, PhD – ichan school of medicine at mount sinai
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 previous studies, we found that the hippocampus (HPC) becomes desynchronized in pilocarpine-treated epileptic mice. The medial entorhinal cortex (MEC) is the upstream region that sends spatial inputs to HPC, suggesting that changes in MEC may mediate downstream effects in HPC. However, it remains unclear how the MEC-HPC circuit is altered following epileptogenesis. Cognitive processes require precise communication between circuits suggesting that altered timing between MEC and HPC may contribute to the cognitive deficits associated with TLE. In a recent study, we found that progressive spatial memory deficits emerge in epileptic mice between three and eight weeks after pilocarpine treatment. In this study, we tested whether MEC-HPC synchronization is disrupted in these 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 (three and eight weeks after pilocarpine) to capture synchronization changes during the progression of memory impairments.
Results:
Dual-region recording reveals that progressive HPC desynchronization emerges early on at three week post pilocarpine, with reduced theta power and altered interneuron phase locking to theta. In contrast, upstream MEC layer 3 (MEC3) excitatory cells are disrupted later in the development of epilepsy, with reduced theta phase locking relative to CA1 theta. Interestingly, we identified two distinct populations of MEC3 excitatory units, with only one population showing disrupted phase preference. We also examine theta coherence within and between regions, and found similar results. Theta coherence within the HPC was reduced in epileptic mice as early as 3wk after pilocarpine, while theta coherence in MEC and between MEC-HPC was only reduced at the later time point, eight week after pilocarpine.
Conclusions:
Together, this data reveals three main points.
First, both HPC and MEC are desynchronized in the chronic phase of pilocarpine-induced epilepsy. This is indicated by changes in theta power, theta coherence, and the phase locking of single units to theta oscillations.
Second, HPC desynchronization emerges earlier than MEC, matching the timeline of seizure onset and hippocampal interneuron loss.
Third, we identified late onset progressive impairments in the synchrony between the MEC-HPC, as well as within the MEC. These data indicate that epilepsy drives multiple, dissociable changes in HPC-MEC circuits with distinct time courses.
Funding:
R01NS116357 (TS), CURE Taking Flight Award (TS), AES Junior Investigator Award (TS), AES Predoctoral Fellowship (SF)