Traumatic brain injury (TBI) often induces structural damage, disruption of the blood–brain barrier (BBB), neurodegeneration, and dysfunctions of surviving neuronal networks. Nitric oxide (NO) signaling has been suggested to affect brain functions after TBI. The NO exhibits most of its biological effects by activation of the primary targets—guanylyl cyclases (NO-GCs), which exists in two isoforms (NO-GC1 and NO-GC2), and the subsequently produced cyclic guanosine monophosphate (cGMP). However, the specific function of the NO-NO-GCs-cGMP pathway in the context of brain injury is not fully understood. To investigate the specific role of the isoform NO-GC1 early after brain injuries, we performed an in vivo unilateral controlled cortical impact (CCI) in the somatosensory cortex of knockout mice lacking NO-GC1 and their wild-type (WT) littermates. Morphological and electrophysiological changes of cortical neurons located 500 μm distant from the lesion border were studied early (24 h) after TBI. The CCI-operated WT mice exhibited significant BBB disruption, an impairment of dendritic spine morphology, a reduced pre-synaptic glutamate release, and less neuronal activity in the ipsilateral cortical network. The impaired ipsilateral neuronal excitability was associated with increased A-type K⁺ currents (I_A) in the WT mice early after TBI. Interestingly, NO-GC1 KO mice revealed relatively less BBB rupture and a weaker brain edema formation early after TBI. Further, lack of NO-GC1 also prevented the impaired synaptic transmission and network function that were observed in TBI-treated WT mice. These data suggest that NO-GC1 signaling mediates early brain damage and the strength of ipsilateral cortical network in the early phase after TBI.

中文翻译：

---

通过鸟苷酸环化酶异构体 1 的一氧化氮/环磷酸鸟苷信号传导介导创伤性脑损伤后突触传递和脑水肿形成的早期变化

创伤性脑损伤 (TBI) 通常会导致结构损伤、血脑屏障 (BBB) 破坏、神经变性和存活神经元网络的功能障碍。一氧化氮 (NO) 信号传导被认为会影响 TBI 后的大脑功能。NO 通过激活主要靶标——鸟苷酸环化酶 (NO-GCs)（以两种同工型（NO-GC1 和 NO-GC2）存在）和随后产生的环磷酸鸟苷 (cGMP) 来展示其大部分生物学效应。然而，NO-NO-GCs-cGMP 通路在脑损伤背景下的具体功能尚不完全清楚。为了研究同种型 NO-GC1 在脑损伤后早期的具体作用，我们进行了体内缺乏 NO-GC1 的敲除小鼠及其野生型 (WT) 同窝小鼠的体感皮层中的单侧受控皮层冲击 (CCI)。在 TBI 后早期（24 小时）研究了距病灶边界 500 μm 的皮层神经元的形态学和电生理学变化。CCI 操作的 WT 小鼠表现出明显的 BBB 破坏、树突棘形态受损、突触前谷氨酸释放减少以及同侧皮质网络中的神经元活动减少。受损的同侧神经元兴奋性与增加的 A 型 K ⁺电流（I _A) 在 TBI 后早期的 WT 小鼠中。有趣的是，NO-GC1 KO 小鼠在 TBI 后早期表现出相对较少的 BBB 破裂和较弱的脑水肿形成。此外，NO-GC1 的缺乏也阻止了在 TBI 治疗的 WT 小鼠中观察到的突触传递和网络功能受损。这些数据表明NO-GC1信号在TBI后早期介导早期脑损伤和同侧皮质网络的强度。