Authors :
Presenting Author: Paul Philipsberg, BE, MS – Icahn School of Medicine at Mount Sinai
Emanuel Coleman, BS – Icahn School of Medicine at Mount Sinai
Zoé Christenson Wick, PhD – Icahn School of Medicine at Mount Sinai
Yu Feng, PhD – Icahn School of Medicine at Mount Sinai
Kaylin Pimshan, – Icahn School of Medicine at Mount Sinai
Cassidy Kohler, BS – Icahn School of Medicine at Mount Sinai
Clifford Kentros, PhD – Norwegian University of Science and Technology
Tristan Shuman, PhD – Icahn School of Medicine at Mount Sinai
Rationale:
Type 2 dentate spikes (DS2s) are synchronizing events thought to be important for spatial memory in the healthy brain. Medial perforant path projections have long been thought to drive DS2s, however the specific contribution of medial entorhinal layer 2 (MEC2) stellate cells to DS2s has never been experimentally tested. Further, the extent to which mechanisms driving dentate spikes in heathy animals are coopted to produce pathological hypersynchronous events in epileptic animals remains unknown. Here we characterize dentate spikes and MEC2 excitatory firing in both healthy and epileptic mice, and optogenetically activate MEC2 stellate cells to elicit DS2-like events and pathological interictal epileptiform discharges (IEDs).
Methods:
We used dual-region silicon probe recordings in MEC and hippocampus to examine neural activity during dentate spikes in both heathy and chronically epileptic mice. We expressed ChR2 specifically in MEC2 stellate cells in order to optogenetically identify them and directly investigate their role in initiating DS2s.
Results:
We found that the firing rates of MEC2 excitatory cells increase preceding a DS2 and that this modulation of firing rate is increased in epileptic mice, which also have higher rates of DS2s. Further, we show that optotagged MEC2 stellate cells increase in firing rate more than non-optotagged MEC2 excitatory neurons. Finally, we show that activating MEC2 stellate cells can elicit DS2-like events, while stimulating with higher light power can drive IEDs even in control animals.
Conclusions:
These results provide new evidence that MEC2 stellate cell activity contributes both to physiological DS2s and is sufficient to induce pathological hypersynchronous events in epilepsy. This provides a novel therapeutic target for treating hypersynchrony contributing to seizures and cognitive impairments in temporal lobe epilepsy.
Funding: NIH grant F31 NS134301, CURE Taking Flight Award, AES Junior Investigator Award, NIH grants R01 NS116357, R01 NS136590, RF1 AG072497, R03 NA111493, R21 DA049568