Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, USA.
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, USA.
Exp Neurol. 2024 Jun;376:114752. doi: 10.1016/j.expneurol.2024.114752. Epub 2024 Mar 12.
Dendritic spines play a pivotal role in synaptic communication and are crucial for learning and memory processes. Abnormalities in spine morphology and plasticity are observed in neurodevelopmental and neuropsychiatric disorders, yet the underlying signaling mechanisms remain poorly understood. The microtubule affinity regulating kinase 1 (MARK1) has been implicated in neurodevelopmental disorders, and the MARK1 gene shows accelerated evolution in the human lineage suggesting a role in cognition. However, the in vivo role of MARK1 in synaptogenesis and cognitive functions remains unknown. Here we show that forebrain-specific conditional knockout (cKO) of Mark1 in mice causes defects in dendritic spine morphogenesis in hippocampal CA1 pyramidal neurons with a significant reduction in spine density. In addition, we found loss of MARK1 causes synaptic accumulation of GKAP and GluA2. Furthermore, we found that MARK1 cKO mice show defects in spatial learning in the Morris water maze and reduced anxiety-like behaviors in the elevated plus maze. Taken together, our data show a novel role for MARK1 in regulating dendritic spine morphogenesis and cognitive functions in vivo.
树突棘在突触通讯中起着关键作用，对于学习和记忆过程至关重要。在神经发育和神经精神疾病中观察到树突棘形态和可塑性的异常，但其潜在的信号机制仍知之甚少。微管亲和调节激酶 1（MARK1）已被牵连到神经发育障碍中，MARK1 基因在人类谱系中表现出加速进化，表明其在认知中的作用。然而，MARK1 在突触发生和认知功能中的体内作用尚不清楚。在这里，我们表明，在小鼠中，大脑前部特异性条件敲除（cKO）Mark1 导致海马 CA1 锥体神经元树突棘形态发生缺陷，树突棘密度显著降低。此外，我们发现 MARK1 的缺失导致 GKAP 和 GluA2 的突触积累。此外，我们发现 MARK1 cKO 小鼠在 Morris 水迷宫中的空间学习中存在缺陷，并且在高架十字迷宫中的焦虑样行为减少。总之，我们的数据表明 MARK1 在调节体内树突棘形态发生和认知功能方面发挥了新的作用。
