Abstracts

Rationale: Spike and wave discharges (SWDs) comprise the hallmark electrographic finding in absence epilepsy (AE). While not directly involved in the genesis of SWDs, preclinical data implicate the basal ganglia (BG) as a seizure modulatory network in AE. Disarrayed firing in the substantia nigra pars reticulata (SNpr), a direct tonic gate of thalamic activity, consistently accompanies SWDs in preclinical models of AE. Tonic activity in the SNpr is modulated by input from the striatum. Two divergent striatal output pathways gate activity in the SNpr: the canonical direct and indirect pathways. Here, using an optogenetic approach, we assessed the roles of the dorsal striatum and its divergent outputs in the modulation of SWDs evoked by systemic administration of gamma-butyrolactone in rats. To modulate direct pathway neurons we expressed opsins in dopamine receptor D1 (DRD1) containing neurons; to modulate the indirect pathway we expressed opsin in dopamine receptor D2 (DRD2).  Methods: Adult male Sprague-Dawley (SD) and Long-Evans (LE) rats received stereotaxic injections of activating opsins (hChR2(H134R) or Chronos) bilaterally in striatum to achieve the capability for pan-neuronal striatal activation. Adult male DRD1- and DRD2-cre rats on LE background obtained from NIDA were injected with cre-restricted opsins to genetically dissect direct and indirect pathways, respectively. Direct pathway SPNs (in DRD1-cre rats) were activated via FLEx-Chronos, while the indirect pathway (specifically striatopallidal SPNs in DRD2-cre rats) was silenced via FLEx-ArchT. All animals were outfitted with fiber optics bilaterally at the striatal injection sites. EEG activity was monitored via epidural electrodes. Animals were injected with GBL (100mg/kg in saline; IP) to evoke SWDs and tested on a within-subject basis with and without light delivery. Additionally, we employed a closed-loop stimulation protocol in which light was delivered to a subset of seizures electrographically detected during the session. Results: Pan-neuronal optogenetic activation of rat striatum (n=6) suppresses incidence of SWDs (p=0.017) and seizure burden (p=0.020). Direct pathway activation (n=4) does not alter course of SWDs. Indirect pathway silencing (n=4) under closed-loop, feedback-dependent photostimulation yielded a reduction in mean SWD duration (p=.045).  Conclusions: Results described in the current study indicate that the dorsal striatum is capable of restraining SWDs generated in the corticothalamocortical loop; however, neural subpopulations contribute differently to this effect.  Funding: NIH R01 NS097762 to PAF.