Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Theranostics. 2024 Oct 7;14(16):6373-6391. doi: 10.7150/thno.96598. eCollection 2024.
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 Ca influx)-mediated sonogenetics (MG-SOG) in a mouse model of kainic acid (KA)-induced SE. 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. 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. 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.
声遗传学是一种基于超声的神经刺激方法，用于靶向特定脑区的神经元。然而，声遗传学在治疗癫痫持续状态（SE）中的作用尚不清楚。在这里，我们旨在研究超声神经刺激和 MscL-G22S（一种介导 Ca2+内流的机械敏感离子通道）介导的声遗传学（MG-SOG）在红藻氨酸（KA）诱导的 SE 小鼠模型中的作用。对于 MG-SOG，将 Cre 依赖性 AAV 表达 MscL-G22S 注射到 PV-cre 和 SST-cre 小鼠中，以分别在 PV 中间神经元（PV-INs）和 SST 中间神经元（SST-INs）中诱导 MscL-G22S-EGFP 的表达；在 SE 模型小鼠的全身性发作（GSs）潜伏期和 SE 潜伏期期间，用连续脉冲超声刺激来刺激小鼠。我们进行钙光纤光度法、膜片钳记录、局部场电位记录和 SE 监测，以研究 MG-SOG 在治疗 SE 中的作用。首先，我们观察到 SE 模型小鼠海马 CA1 区明显的神经元激活。CA1 区的兴奋性神经元（ENs）和 GABA 能中间神经元（GABA-INs）均在 SE 模型小鼠中被激活；然而，尽管 SE 模型小鼠中 GABA-INs 的激活增加，但 GABA-INs 对 ENs 的抑制作用似乎不足以降低 ENs 的兴奋性。因此，我们推测 CA1 区 MG-SOG 诱导的 GABA-INs（主要是 SST-INs 和 PV-INs）的激活可能对 SE 具有保护作用。我们发现，CA1 区 MG-SOG 介导的 PV-IN 激活改善了 SE，并改变了 CA1 区与 SE 相关的电生理异常；然而，CA1 区 MG-SOG 诱导的 SST-IN 激活并没有改善 SE。MG-SOG 介导的 PV-IN 激活对缓解 SE 有积极作用。我们的工作可能会促进声遗传神经刺激技术治疗 SE 的发展。
