Mottolese Nicola, Iannibelli Feliciana, Candini Giulia, Trebbi Federica, Loi Manuela, Bove Angelica Marina, Medici Giorgio, Xiong Zhi-Qi, Ciani Elisabetta, Trazzi Stefania
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.
State Key Laboratory of Neuroscience, Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China.
Int J Mol Sci. 2025 Jul 10;26(14):6626. doi: 10.3390/ijms26146626.
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental condition characterized by early-onset, intractable epilepsy, motor and cognitive impairment, and autistic-like features. Although constitutive knockout (KO) models have established the importance of CDKL5 during early brain development, CDKL5's role in the mature brain remains poorly defined. Here, we employed an inducible, conditional KO model in which is selectively deleted from forebrain glutamatergic neurons in adult mice to investigate the postdevelopmental functions of CDKL5. Using a total of 48 adult male mice, including (Cre) ( = 30) and (Cre) littermate controls ( = 18), we found that tamoxifen-induced deletion led to prominent behavioral impairments, including deficits in motor coordination, reduced sociability, and impaired hippocampus-dependent spatial memory, while behavioral features such as hyperactivity and stereotypic jumping, typically present in germline KOs, were absent. Sensory functions, including olfaction and pain perception, were also preserved. At the cellular level, the loss of Cdkl5 resulted in a marked reduction in excitatory synapse density in the cortex and hippocampus, accompanied by increased numbers of immature dendritic spines and decreased mature spines. Neuronal loss in the hippocampal CA1 region and selective microglial activation in the cortex were also observed. These alterations closely resemble those seen in constitutive KO models, underscoring the ongoing requirement for CDKL5 expression in excitatory neurons for maintaining synaptic integrity and neuronal homeostasis in the adult brain. This study underscores the importance of temporally controlled models for investigating the mechanisms underlying CDD pathophysiology in the adult brain.
细胞周期蛋白依赖性激酶样5（CDKL5）缺陷障碍（CDD）是一种严重的X连锁神经发育疾病，其特征为早发性、难治性癫痫、运动和认知障碍以及类自闭症特征。尽管组成型基因敲除（KO）模型已证实CDKL5在早期脑发育过程中的重要性，但其在成熟大脑中的作用仍不清楚。在此，我们采用了一种诱导性条件性KO模型，其中在成年小鼠前脑谷氨酸能神经元中选择性删除，以研究CDKL5的发育后功能。我们总共使用了48只成年雄性小鼠，包括（Cre）（ = 30）和（Cre）同窝对照（ = 18），我们发现他莫昔芬诱导的删除导致了明显的行为障碍，包括运动协调缺陷、社交性降低以及海马依赖性空间记忆受损，而种系KO中通常出现的多动和刻板跳跃等行为特征则不存在。嗅觉和疼痛感知等感觉功能也得以保留。在细胞水平上，Cdkl5的缺失导致皮质和海马中兴奋性突触密度显著降低，同时未成熟树突棘数量增加，成熟棘数量减少。还观察到海马CA1区的神经元丢失和皮质中的选择性小胶质细胞激活。这些改变与组成型KO模型中所见的改变非常相似，强调了成年大脑中兴奋性神经元持续表达CDKL5对于维持突触完整性和神经元稳态的必要性。这项研究强调了时间控制模型对于研究成年大脑中CDD病理生理学潜在机制的重要性。
