Abstracts

Rationale: Novel treatment strategies are needed for temporal lobe epilepsy (TLE) as one third of patients do not achieve seizure control with current medications or surgical procedures. Medial septum GABAergic projection neurons (MSGPNs) specifically target GABAergic cells throughout the hippocampal formation and can generate and modulate hippocampal theta oscillations (4-12 Hz). MSGPNs exert a powerful influence over network activity in the hippocampal formation, which are seizure generating areas in TLE. Our aim is to determine whether modulation of the activity of MSGPNs could be a viable therapeutic target to treat TLE. Methods: We have characteriszd MSGPN projections to the hippocampus in the mouse intrahippocampal chronic model of epilepsy. We utilized VGAT::Cre mice in combination with viral injections to express cre-dependant fluorescent proteins GFP, in axons, and mRuby tagged to synaptophysin, in putative synaptic terminals. In separate experiments we expressed channelrhodopsin-2 in MSGPNs and assessed whether local field potential oscillations recorded across the hippocampus could be entrained before and after epilepsy upon optical stimulation. Finally, we are testing whether wireless optogenetic stimulation of MSGPNs modulates seizure duration. Results: Parvalbumin, calbindin and VGAT positive MSGPN populations are unaffected by chronic epileptic conditions 3 weeks after kainate injections (n=4 animals) when compared with saline controls (n=3, p=>0.1 for all neuronal populations). We also found intact projections and putative synaptophysin tagged boutons from MSGPNs at 4 locations along the dorsal to caudal extent of the ipsilateral and contralateral hippocampi (n=5 for both kainate and saline treated groups, p=>0.05). Furthermore, we can entrain theta oscillations across the hippocampal formation by optogenetically stimulating MSGPNs expressing channelrhodopsin-2 with 10 Hz square pulses before and after chronic seizures are established. There is an increase in the ratio of the stimulation frequency with optical stimulation both in control and chronic epilepsy conditions (n=3, p=<0.02). We are testing whether 10 Hz optogenetic stimulation upon online seizure identification decreases seizure duration when compared to no-stimulation conditions. Conclusions: Based on these findings, we hypothesise that by optogenetically modulating the activity of MSGPNs we will be able to control oscillations in chronically epileptic animals and change seizure dynamics across the hippocampal formation. We propose MSGPN specific stimulation as a potential novel therapeutic strategy to attain seizure control in patients with TLE. This type of stimulation may be implemented through genetic therapy or deep brain stimulation. Funding: Epilepsy Research UK, Simons Initiative for the developing brain.