Gui_2026_Transl.Psychiatry__

Ischemic injury has been reported to induce mild to severe permanent deficits. Nevertheless, its recovery is often dynamic, depending on the plasticity of the injured neurons. The current study found that during the early stage of cerebral ischemia (1 h), Npas4 expression was increased in the hippocampus of mice, thereby transcriptionally regulated the expression of Neuroligin-1 and N-cadherin to enhance long-term potentiation. Knocking down of Npas4 reduced the level of Neuroligin-1 and N-cadherin, sequentially prevented the enhanced neural plasticity in the early cerebral ischemia. Furthermore, the downregulation of Neuroligin-1 and N-cadherin also impeded the ischemia-induced enhancement in neural plasticity without affecting the expression of Npas4. Overexpression of Npas4 in the primary neurons increased the number of VAMP2-labeled synaptic vesicles, while interfering the expression of Neuroligin-1 and N-cadherin in the primary neurons with siRNA reduced the increase of VAMP2-labeled synaptic vesicles without affecting the Npas4 expression. Interestingly, the transcriptional level of Npas4, Neuroligin-1, and N-cadherin declined in multiple brain regions of Alzheimer's disease (AD) patients and 3 x TG AD mice. Moreover, overexpression of Npas4 increased the expression of Neuroligin-1 and N-cadherin, ameliorated the synaptic plasticity impairment of 3 x TG mice, and enhanced the cognitive function. These findings suggest a previously undiscovered biological mechanism of neural plasticity, driven by Npas4 upregulation of Neuroligin-1 and N-cadherin, which partially explain why the compensatory increase in Npas4 in the early stages of ischemic injury and the lack of Npas4 in AD progression, highlighting potential therapeutic strategies for cognitive deficits.