Department of Otorhinolaryngology-Head & Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Otorhinolaryngology-Head & Neck Surgery, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China.
FEBS J. 2023 Aug;290(16):4092-4106. doi: 10.1111/febs.16799. Epub 2023 May 10.
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 K 4.3 expression. A-type potassium currents were enhanced, and K 4.3 participated in blocking excitatory presynaptic inputs. Elevated K 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.
神经元兴奋性是中枢神经系统发育的关键特征，在大脑区域的功能成熟中起着根本性作用，包括海马体、小脑、听觉和视觉系统。本研究旨在通过在缺氧新生小鼠模型中扰乱神经元兴奋性，确定缺氧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大脑发育。在小鼠中，通过 mRNA 测序和定量 PCR 评估基因转录；此外，通过膜片钳记录评估钾电流。临床观察发现，缺氧新生儿在 6 个月和 18 个月时出现功能性大脑发育障碍，而那些出生时听力筛查正常的婴儿在 3 个月时表现出中枢听觉功能受损。在模型小鼠中，CA1 锥体神经元的自发活动减少，主要是由于兴奋性突触输入抑制所致，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，证实了海马体 K 4.3 表达上调。A 型钾电流增强，K 4.3 参与阻断兴奋性突触前输入。在缺氧条件下，锥体神经元中升高的 K 4.3 活性抑制兴奋性突触前输入，进一步降低神经元兴奋性，破坏缺氧新生儿的功能性大脑发育。
