Department of Neurology, Ulm University, Ulm-DE, Germany.
Department of Neurobiology-IZN, Heidelberg University, Heidelberg-DE, Germany.
Cereb Cortex. 2019 Jun 1;29(6):2701-2715. doi: 10.1093/cercor/bhy139.
Excessive excitation has been hypothesized to subsume a significant part of the acute damage occurring after traumatic brain injury (TBI). However, reduced neuronal excitability, loss of neuronal firing, and a disturbed excitation/inhibition balance have been detected. Parvalbumin (PV) interneurons are major regulators of perisomatic inhibition, principal neurons firing, and overall cortical excitability. However, their role in acute TBI pathogenic cascades is unclear. We exploited the chemogenetic Pharmacologically Selective Activation Module and Pharmacologically Selective Effector Module control of PV-Cre+ neurons and the Designer Receptors Exclusively Activated by Designer Drug (DREADD) control of principal neurons in a blunt model of TBI to explore the role of inhibition in shaping neuronal vulnerability to TBI. We demonstrated that inactivation of PV interneurons at the instance or soon after trauma enhances survival of principal neurons and reduces gliosis at 7 dpi whereas, activation of PV interneurons decreased neuronal survival. The protective effect of PV inactivation was suppressed by expressing the nuclear calcium buffer PV-nuclear localisation sequence in principal neurons, implying an activity-dependent neuroprotective signal. In fact, protective effects were obtained by increasing the excitability of principal neurons directly using DREADDs. Thus, we show that sustaining neuronal excitation in the early phases of TBI may reduce neuronal vulnerability by increasing activity-dependent survival, while excess activation of perisomatic inhibition is detrimental to neuronal integrity.
过度兴奋被认为包含了创伤性脑损伤 (TBI) 后急性损伤的很大一部分。然而，已经检测到神经元兴奋性降低、神经元放电丧失以及兴奋/抑制平衡紊乱。PV 中间神经元是躯体抑制、主要神经元放电和整体皮质兴奋性的主要调节因子。然而，它们在急性 TBI 发病机制中的作用尚不清楚。我们利用化学遗传 Pharmacologically Selective Activation Module 和 Pharmacologically Selective Effector Module 对 PV-Cre+神经元的控制，以及 Designer Receptors Exclusively Activated by Designer Drug (DREADD) 对主要神经元的控制，在 TBI 的钝性模型中探索了抑制在塑造神经元对 TBI 的易损性中的作用。我们证明，在创伤发生时或之后立即抑制 PV 中间神经元会增加主要神经元的存活并减少 7dpi 时的神经胶质增生，而激活 PV 中间神经元会减少神经元存活。在主要神经元中表达核钙缓冲剂 PV-核定位序列会抑制 PV 失活的保护作用，这表明存在一种依赖于活性的神经保护信号。事实上，通过使用 DREADD 直接增加主要神经元的兴奋性可以获得保护作用。因此，我们表明，在 TBI 的早期阶段维持神经元兴奋可能通过增加依赖于活性的存活来降低神经元的脆弱性，而过度激活躯体抑制对神经元完整性是有害的。
