Institute of Neuroscience, and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY, 10016, USA.
Nat Commun. 2018 Jun 22;9(1):2451. doi: 10.1038/s41467-018-04705-8.
Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca/CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes (BDNF, c-Fos, Arc), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.
学习和记忆依赖于源自突触的神经元可塑性，并且需要核基因表达才能持续。然而，突触到细胞核的通讯如何支持长期的可塑性和行为仍然难以捉摸。在细胞质核信号蛋白中，γCaMKII 因其能够快速将 Ca/CaM 转运到细胞核并激活 CREB 依赖性转录而引人注目。在这里，我们表明，消除 γCaMKII 会阻止关键基因（BDNF、c-Fos、Arc）的活性依赖性表达，抑制持久的突触增强，并损害体内的空间记忆。在成年兴奋性神经元中删除 γCaMKII 会产生类似的效果。γCaMKII 中的一个点突变，先前在智力障碍的病例中被发现，选择性地破坏了 CaM 隔离和 CaM 穿梭。值得注意的是，这种突变足以破坏体内的基因表达和空间学习。因此，这种特定形式的细胞质核信号在学习和记忆中起着关键作用，并导致神经精神疾病。
