Authors :
Presenting Author: Carolina Campos-Rodriguez, MSc, PhD – Georgetown University
Victor Santos, PhD – Pharmacology & Physiology – Georgetown University; Anjik Ghosh, MS – Pharmacology and Physiology – Georgetown University; Marc Comair, BS – Pharmacology and Physiology – Georgetown University; Patrick Forcelli, PhD – Pharmacology and Physiology – Georgetown University
Rationale:
The pedunculopontine nucleus (PPN) is a brainstem nucleus that regulates cortical rhythms through glutamatergic (Glu) and cholinergic outputs to the thalamus, brainstem, and basal forebrain. Given its central role in arousal and potent effects on cortical synchronization, we tested whether activation or inactivation of Glu neurons of the PPN would disrupt absence seizures.
Methods: Long Evans (LE) naïve rats (males) and Wistar Albino Glaxo Rats from Rijswijk (WAG/Rij; males and females) were injected with virus coding for either channelrhodopsin-2 or an archaerhodopsin-3 and implanted with fiber optics bilaterally in the PPN and cortical EEG electrodes. Three weeks post-surgery, they were tested on open-loop (i.e., continuous neuromodulation) and closed-loop (i.e., on-demand neuromodulation, stimulation at the time of seizure detection) stimulation paradigms at three different light frequencies: 5, 20, 100 Hz. LE animals received a systemic injection of gamma-butyrolactone (GBL 100 mg/kg) prior to the stimulation to induce absence-like seizures. Spike-wave discharges (SWDs) were detected by cortical EEGs, recorded for 30 min after the injection for the open loop paradigm and 60 min for the on-demand stimulation. For the WAG/Rij rats, cortical-EEGs were recorded for two hours in both stimulation protocols.
Results:
The continuous optogenetic activation or inactivation of Glu neurons in the GBL model did not reduce the duration or number of spike-wave discharges (SWDs), something similar occurs in the WAG/Rij rats independent of the sex. The on-demand paradigm was more effective. Optogenetic activation of Glu transmission decreased the duration of SWDs at 5 Hz in both models of absence seizures. However, the optogenetic inactivation of PPN did not abolish seizures either in the acute or genetic model of absence epilepsy at any frequency applied.
Conclusions: Neuromodulation of the glutamatergic PPN cells exerts absence anti-seizure effects and stimulation modality specific manner. On-demand stimulation was the optimal strategy when activating Glu pathways, while continuous activation was ineffective. This suggests that the pattern of stimulation may be a critical determinant of this anti-seizure effect.
Funding: R01NS097762-06