Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca²⁺-permeable AMPA receptor upregulation, L-type Ca²⁺ channel activation, enhanced spine Ca²⁺ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.

神经放电特性的稳态对于稳定神经元回路很重要，但这种可塑性如何取决于选择性剪接尚不清楚。在这里，我们报告慢性不活动通过改变 BK 通道的可变剪接来增加动作电位持续时间。这需要剪接因子 Nova-2 的核输出。不活动和 Nova-2 重新定位通过一种新的突触核信号通路连接起来，该通路令人惊讶地调用了类似于 Hebbian 可塑性的机制：Ca ²⁺渗透性 AMPA 受体上调、L 型 Ca ²⁺通道激活、脊柱 Ca ^2+增强瞬变、CaM 穿梭的核转位和核 CaMKIV 激活。这些发现不仅揭示了稳态和赫布可塑性之间的共同点，而且还将突触传递的稳态调节和神经元兴奋性联系起来。信号级联为 25 年前提出的经典自动调节反馈回路提供了全回路机制。循环的每个元素以前都与神经精神疾病有关。