Targeted sonogenetic modulation of GABAergic interneurons in the hippocampal CA1 region in status epilepticus

Rationale: Sonogenetics is an advanced ultrasound-based neurostimulation approach for targeting neurons in specific brain regions. However, the role of sonogenetics in treating status epilepticus (SE) remains unclear. Here, we aimed to investigate the effects of ultrasound neurostimulation and MscL-G22S (a mechanosensitive ion channel that mediates CA²⁺ influx)-mediated sonogenetics (MG-SOG) in a mouse model of kainic acid (KA)-induced SE. Methods: For MG-SOG, a Cre-dependent AAV expressing MscL-G22S was injected into parvalbumin (PV)-cre and somatostatin (SST)-cre mice to induce the expression of MscL-G22S-EGFP in PV interneurons (PV-INs) and SST interneurons (SST-INs), respectively; mice were stimulated with continuous pulses of ultrasound stimulation during the latency of generalized seizures (GSs), the latency to SE, in SE model mice. We performed calcium fiber photometry, patch-clamp recording, local field potential recording, and SE monitoring to investigate the role of MG-SOG in treating SE. Results: First, we observed obvious neuronal activation in the hippocampal CA1 region in SE model mice. Both excitatory neurons (ENs) and GABAergic interneurons (GABA-INs) in the CA1 region were activated in SE model mice; however, the inhibitory effect of GABA-INs on ENs seemed to be insufficient to reduce EN excitability despite the increased activation of GABA-INs in SE model mice. Thus, we speculated that MG-SOG-induced activation of GABA-INs, mainly SST-INs and PV-INs, in the CA1 region may protect against SE. We found that MG-SOG-mediated PV-IN activation in the CA1 region ameliorated SE and changed SE-related electrophysiological abnormalities in the CA1 region; however, MG-SOG-induced SST-IN activation in the CA1 region did not ameliorate SE. Conclusions: MG-SOG-mediated activation of PV-INs had a positive effect on relieving SE. Our work may promote the development of sonogenetic neurostimulation techniques for treating SE.

hippocampus; parvalbumin interneurons; somatostatin interneurons; sonogenetic; status epilepticus.