An Inhibitory Nigra-parafascicular Pathway Mediates The Development Of Temporal Lobe Epilepsy

The substantia nigra pars reticulata(SNr),a region that mainly contains GABAergic neurons,is thought to be involved in epilepsy,but its precise cellular and neuronal circuitry mechanisms in temporal lobe epilepsy(TLE)have not been investigated.Using single-unit recordings and calcium fiber photometry,we found that SNr GABAergic/parvalbumin(PV)neurons were activated during seizures.Optogenetic and chemogenetic inhibition of SNr PV neurons retarded the development of TLE,whereas activation of these neurons promoted the development of TLE.In addition,epilepsy was bilaterally regulated by optogenetic manipulation of SNr PV projection fibers in the parafascicular nucleus(PF),but not in the reticularis nucleus(RT)or the reuniens nucleus(RE).Furthermore,in vivo/in vitro electrophysiology combined with rabies virus-assisted circuit-mapping,showed that SNr PV neurons directly project to PF GABAergic neurons.Finally,optogenetic manipulation of PF GABAergic neurons mimicked the role of PF-projecting PV fibers from the SNr in the development of TLE.Optogenetic activation of PF GABAergic neurons retarded the development of TLE,whereas inhibition of these neurons promoted the development of TLE.Collectively,our results revealed a previously unknown neural pathway,originating from SNr PV neurons to PF GABAergic neurons,involved in TLE.These findings are relevant for a better understanding of pathological network changes and might provide new insight for therapeutic manipulations in TLE.