Abstract
The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear. Here we found that optogenetic or chemogenetic activation of SNr parvalbumin+ (PV) GABAergic neurons amplifies seizure activities in kindling- and kainic acid-induced TLE models, whereas selective inhibition of these neurons alleviates seizure activities. The severity of seizures is bidirectionally regulated by optogenetic manipulation of SNr PV fibers projecting to the parafascicular nucleus (PF). Electrophysiology combined with rabies virus-assisted circuit mapping shows that SNr PV neurons directly project to and functionally inhibit posterior PF GABAergic neurons. Activity of these neurons also regulates seizure activity. Collectively, our results reveal that a long-range SNr-PF disinhibitory circuit participates in regulating seizure in TLE and inactivation of this circuit can alleviate severity of epileptic seizures. These findings provide a better understanding of pathological changes from a circuit perspective and suggest a possibility to precisely control epilepsy.
Highlights
The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear
To examine the function of SNr GABAergic neurons in relation to seizure in TLE, we recorded the firing activity of SNr putative GABAergic neurons and local field potentials (LFPs) in anesthetized mice using in vivo single-unit recording
We found that photo-activation of SNr-parafascicular nucleus (PF) PV axons reliably and quickly inhibited the firing rate of 6/12 putative GABAergic neurons recorded in the PF (Fig. 5b)
Summary
The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear. Experimental studies have reported structural and functional changes of SNr neurons among different types of epileptic models[14,15,16,17,18] In addition to those findings, lesion[19], pharmacological interference[20,21,22,23,24], or deep brain stimulation[25,26] targeting the SNr can modulate the intensity of epileptic seizures, suggesting that the SNr plays a key role in seizure control. Subsequent in vivo and in vitro electrophysiology combined with rabies virus-assisted circuit mapping revealed that SNr PV neurons form structural and functional connection with neurons in the parafascicular nucleus (PF), some of which form the nigraparafascicular disinhibitory circuit that is involved in bidirectional modulation of seizures in TLE
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