Abstract：
Neuronal excitability is a critical feature of central nervous system development, playing a fundamental role in the functional maturation of brain regions, including the hippocampus, cerebellum, auditory and visual systems. The present study aimed to determine the mechanism by which hypoxia causes brain dysfunction through perturbation of neuronal excitability in a hypoxic neonatal mouse model. Functional brain development was assessed in humans using the Gesell Development Diagnosis Scale. In mice, gene transcription was evaluated via mRNA sequencing and quantitative PCR; furthermore, patch clamp recordings assessed potassium currents. Clinical observations revealed disrupted functional brain development in 6- and 18-month-old hypoxic neonates, and those born with normal hearing screening unexpectedly exhibited impaired central auditory function at 3 months. In model mice, CA1 pyramidal neurons exhibited reduced spontaneous activity, largely induced by excitatory synaptic input suppression, despite the elevated membrane excitability of hypoxic neurons compared to that of control neurons. In hypoxic neurons, Kcnd3 gene transcription was upregulated, confirming upregulated hippocampal Kv 4.3 expression. A-type potassium currents were enhanced, and Kv 4.3 participated in blocking excitatory presynaptic inputs. Elevated Kv 4.3 activity in pyramidal neurons under hypoxic conditions inhibited excitatory presynaptic inputs and further decreased neuronal excitability, disrupting functional brain development in hypoxic neonates.
摘要：
神经元兴奋性是中枢神经系统发育的重要特征,在大脑区域的功能成熟中起着重要作用，包括海马,小脑,听觉和视觉系统。本研究旨在确定缺氧新生小鼠模型中缺氧通过干扰神经元兴奋性而导致脑功能障碍的机制。使用Gesell发育诊断量表评估人类的功能性脑发育。在老鼠身上,通过mRNA测序和定量PCR评估基因转录；此外，膜片钳记录评估钾电流。临床观察显示，6个月和18个月大的缺氧新生儿的脑功能发育中断，听力筛查正常的人在3个月时意外表现出中枢听觉功能受损。在模型小鼠中，CA1锥体神经元表现出减少的自发活动，主要由兴奋性突触输入抑制引起，尽管与对照神经元相比，缺氧神经元的膜兴奋性升高。在缺氧神经元中，Kcnd3基因转录上调,证实海马Kv4.3表达上调。A型钾电流增强，Kv4.3参与阻断兴奋性突触前输入。在低氧条件下，锥体神经元的Kv4.3活性升高抑制了兴奋性突触前输入，并进一步降低了神经元的兴奋性，缺氧新生儿大脑功能发育中断.
