Abstracts

Rationale: Current anti-seizure drugs target ligand- or voltage-gated membrane channels to dampen excitation or augment inhibition. Unfortunately however, despite the availability of numerous medications developed using this therapeutic rationale, up to one-third of patients with epilepsy cannot achieve adequate seizure control.  Methods: Here we describe an alternative approach in which parvalbumin-positive (PV+) inhibitory interneurons are directly stimulated using the designer receptors exclusively activated by designer drugs (DREADD) system. Adeno-associated virus loaded with a construct that confers Cre recombinase-dependent expression of an activating DREADD receptor was injected into the bilateral frontal neocortex of mouse pups that will express Cre in PV+ interneurons. In adulthood, susceptibility to pentylenetetrazole-triggered seizures was tested after systemic administration of the DREADD ligand Clozapine-N-Oxide. Results: Direct activation of PV+ interneurons prevented generalized tonic clonic seizuers in 100% of animals (p < 0.05), and interestingly also induced a hypomotor state.  Conclusions: These data indicate that PV+ interneurons possess significant inhibitory reserve that can be leveraged in seizure prevention by directly stimulating their activity. Importantly, in contrast to optogenetic approaches, regulation of PV+ interneuron activity here is achieved though systemic drug delivery and does not require hardware implantation. Funding: NIH NINDS R25 2R25NS070682-06 (PIs: Drs. Scott Pomeroy & Clifford Saper, Awardee: Johnson)NIH NINDS R01 NS088583 (PI: Dr. Alexander Rotenberg)