Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China.
Genes Brain Behav. 2023 Dec;22(6):e12863. doi: 10.1111/gbb.12863. Epub 2023 Aug 14.
An environmental risk factor for schizophrenia (SZ) is maternal infection, which exerts longstanding effects on the neurodevelopment of offspring. Accumulating evidence suggests that synaptic disturbances may contribute to the pathology of the disease, but the underlying molecular mechanisms remain poorly understood. Erythropoietin-producing hepatocellular B (EphB) receptor signaling plays an important role in synaptic plasticity by regulating the formation and maturation of dendritic spines and regulating excitatory neurotransmission. We examined whether EphB receptors and downstream associated proteins are susceptible to environmental risk factors implicated in the etiology of synaptic disturbances in SZ. Using an established rodent model, which closely imitates the characteristics of SZ, we observed the behavioral performance and synaptic structure of male offspring in adolescence and early adulthood. We then analyzed the expression of EphB receptors and associated proteins in the prefrontal cortex and hippocampus. Maternal immune activation offspring showed significantly progressive cognitive impairment and pre-pulse inhibition deficits together with an increase in the expression of EphB2 receptors and NMDA receptor subunits. We also found changes in EphB receptor downstream signaling, in particular, a decrease in phospho-cofilin levels which may explain the reduced dendritic spine density. Besides, we found that the AMPA glutamate, another glutamate ionic receptor associated with cofilin, decreased significantly in maternal immune activation offspring. Thus, alterations in EphB signaling induced by immune activation during pregnancy may underlie disruptions in synaptic plasticity and function in the prefrontal cortex and hippocampus associated with behavioral and cognitive impairment. These findings may provide insight into the mechanisms underlying SZ.
精神分裂症 (SZ) 的一个环境风险因素是母体感染，它对后代的神经发育产生持久影响。越来越多的证据表明，突触紊乱可能导致疾病的病理发生，但潜在的分子机制仍知之甚少。促红细胞生成素产生肝细胞 B (EphB) 受体信号通过调节树突棘的形成和成熟以及调节兴奋性神经传递，在突触可塑性中发挥重要作用。我们研究了 EphB 受体及其下游相关蛋白是否容易受到与 SZ 中突触紊乱病因相关的环境风险因素的影响。我们使用了一种已建立的啮齿动物模型，该模型非常类似于 SZ 的特征，观察了青春期和成年早期雄性后代的行为表现和突触结构。然后，我们分析了前额叶皮层和海马体中 EphB 受体和相关蛋白的表达。母体免疫激活后代表现出明显的进行性认知障碍和前脉冲抑制缺陷，同时 EphB2 受体和 NMDA 受体亚基的表达增加。我们还发现 EphB 受体下游信号发生变化，特别是磷酸化原肌球蛋白水平降低，这可能解释了树突棘密度降低的原因。此外，我们发现与原肌球蛋白相关的 AMPA 谷氨酸，即另一种谷氨酸离子受体，在母体免疫激活后代中显著减少。因此，怀孕期间免疫激活引起的 EphB 信号改变可能是与行为和认知障碍相关的前额叶皮层和海马体中突触可塑性和功能紊乱的基础。这些发现可能为 SZ 的发病机制提供新的见解。
