Entorhinal Principal Neurons Mediate Brain-stimulation Treatments for Epilepsy

Abstract

Brain stimulation is an alternative treatment for epilepsy. However, the neuronal circuits underlying its mechanisms remain obscure. We found that optogenetic activation (1 Hz) of entorhinal calcium/calmodulin-dependent protein kinase II α (CaMKIIα)-positive neurons, but not GABAergic neurons, retarded hippocampal epileptogenesis and reduced hippocampal seizure severity, similar to that of entorhinal low-frequency electrical stimulation (LFES). Optogenetic inhibition of entorhinal CaMKIIα-positive neurons blocked the antiepileptic effect of LFES. The channelrhodopsin-2-eYFP labeled entorhinal CaMKIIα-positive neurons primarily targeted the hippocampus, and the activation of these fibers reduced hippocampal seizure severity. By combining extracellular recording and pharmacological methods, we found that activating entorhinal CaMKIIα-positive neurons induced the GABA-mediated inhibition of hippocampal neurons. Optogenetic activation of focal hippocampal GABAergic neurons mimicked this neuronal modulatory effect and reduced hippocampal seizure severity, but the anti-epileptic effect is weaker than that of entorhinal LFES, which may be due to the limited spatial neuronal modulatory effect of focal photo-stimulation. Our results demonstrate a glutamatergic-GABAergic neuronal circuit for LFES treatment of epilepsy, which is mediated by entorhinal principal neurons.

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy

“…The fewer number of GAD neurons compared with eYFP-labeled neurons was likely due to the detection limitation of GAD antibody. We designed opto-electrodes that allow optogenetic stimulation during in vivo single-unit recordings in the SNr of urethaneanesthetized mice 32 . Representative peri-event histograms confirmed that blue-light stimulation (473 nm, 20 Hz, 10 ms, 5 mW, 10 s on-off cycle) excited 15 out of 19 SNr GABAergic neurons from 3 Vgat-ChR2-eYFP mice, suggesting that SNr GABAergic neurons can be functionally activated by blue-light stimulation.…”

“…The SNr-PF circuit may act like an intrinsic feed-forward amplifier; it may respond to abnormal cortical information input through basal ganglia circuit during seizures (as demonstrated by our fiber photometry showing the increased SNr PV neural dynamics), and thus in turn regulate epileptic networks via thalamocorticalhippocampal circuits. Specifically, connections between the PF and the entorhinal cortex 55 , the major source of cortical projections to the hippocampus 32,58 , are likely involved in these modulatory effects. Although abnormalities in the PF still need to be clarified for a better understanding of the abnormal network in seizure propagation, here we identified inhibition of PF GABAergic neurons by SNr PV projections as an important mechanism allowing for precise regulation of TLE.…”

Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

“…To verify whether the virus was functional in vivo, neuronal spikes were recorded and analyzed in PV-hM3Dq and CaMKII2α-hM4Di mice which were anesthetized by urethane as our previous studies. 28 To test the neuronal response in hippocampal seizure, single-unit recordings were performed and analyzed in urethane-anesthetized wildtype mice. Putative pyramidal neurons and GABAergic neurons were distinguished by three independent criteria (firing rate, spike width, and autocorrelation pattern) based on previous studies.…”

Neural mass modeling of slow-fast dynamics of seizure initiation and abortion

“…For instance, a pre-ictal spiking regime mediated by GABA B interneurons may be aborted by using lower stimulation frequencies than a pre-ictal spiking regime mediated by GABA A interneurons, since GABA B interneurons have slower kinetics than GABA A interneurons. Depending on the neuroanatomy and neurophysiology of a specific brain region (type of subpopulations and connections between them), activation of specific types of interneurons can be achieved via the modulation of different neural targets [57,58,60,[76][77][78].…”