Costa Lara, Tempio Alessandra, Lacivita Enza, Leopoldo Marcello, Ciranna Lucia
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Eur J Neurosci. 2021 May 5;54(1):4124-32. doi: 10.1111/ejn.15246.
Fragile X Syndrome is a genetic form of intellectual disability associated with autism, epilepsy and mood disorders. Electrophysiology studies in Fmr1 knockout (KO) mice, a murine model of Fragile X Syndrome, have demonstrated alterations of synaptic plasticity, with exaggerated long-term depression induced by activation of metabotropic glutamate receptors (mGluR-LTD) in Fmr1 KO hippocampus. We have previously demonstrated that activation of serotonin 5-HT7 receptors reverses mGluR-LTD in the hippocampus of wild-type and Fmr1 KO mice, thus correcting a synaptic dysfunction typically observed in this disease model. Here we show that pharmacological inhibition of cyclin-dependent kinase 5 (Cdk5, a signaling molecule recently shown to be a modulator of brain synaptic plasticity) enhanced mGluR-LTD in wild-type hippocampal neurons, which became comparable to exaggerated mGluR-LTD observed in Fmr1 KO neurons. Furthermore, Cdk5 inhibition prevented 5-HT7 receptor-mediated reversal of mGluR-LTD both in wild-type and in Fmr1 KO neurons. Our results show that Cdk5 modulates hippocampal synaptic plasticity. 5-HT7 receptors require Cdk5 to modulate synaptic plasticity in wild-type and rescue abnormal plasticity in Fmr1 KO neurons, pointing out Cdk5 as a possible novel target in Fragile X Syndrome.
脆性X综合征是一种与自闭症、癫痫和情绪障碍相关的遗传性智力残疾。脆性X综合征的小鼠模型Fmr1基因敲除（KO）小鼠的电生理学研究表明，突触可塑性发生改变，Fmr1基因敲除小鼠海马体中代谢型谷氨酸受体激活（mGluR-LTD）诱导的长时程抑制增强。我们之前已经证明，5-羟色胺5-HT7受体的激活可逆转野生型和Fmr1基因敲除小鼠海马体中的mGluR-LTD，从而纠正这种疾病模型中通常观察到的突触功能障碍。在这里，我们表明，细胞周期蛋白依赖性激酶5（Cdk5，一种最近被证明是脑突触可塑性调节剂的信号分子）的药理学抑制增强了野生型海马神经元中的mGluR-LTD，这与在Fmr1基因敲除神经元中观察到的增强的mGluR-LTD相当。此外，Cdk5抑制阻止了野生型和Fmr1基因敲除神经元中5-HT7受体介导的mGluR-LTD逆转。我们的结果表明，Cdk5调节海马体突触可塑性。5-HT7受体需要Cdk5来调节野生型中的突触可塑性，并挽救Fmr1基因敲除神经元中的异常可塑性，指出Cdk5可能是脆性X综合征的一个新靶点。
