Matteoli Gabriele, Alvente Sara, Bastianini Stefano, Berteotti Chiara, Ciani Elisabetta, Cinelli Elenia, Lo Martire Viviana, Medici Giorgio, Mello Tommaso, Miglioranza Elena, Silvani Alessandro, Mutolo Donatella, Zoccoli Giovanna
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
Department of Experimental and Clinical Medicine, Section of Physiology, University of Florence, Florence, Italy.
J Sleep Res. 2025 Apr;34(2):e14295. doi: 10.1111/jsr.14295. Epub 2024 Jul 24.
CDKL5 deficiency disorder is a rare genetic disease caused by mutations in the CDKL5 gene. Central apneas during wakefulness have been reported in patients with CDKL5 deficiency disorder. Studies on CDKL5-knockout mice, a CDKL5 deficiency disorder model, reported sleep apneas, but it is still unclear whether these events are central (central sleep apnea) or obstructive (obstructive sleep apnea) and may be related to alterations of brain circuits that modulate breathing rhythm. This study aimed to discriminate central sleep apnea and obstructive sleep apnea in CDKL5-knockout mice, and explore changes in the somatostatin neurons expressing high levels of neurokinin-1 receptors within the preBötzinger complex. Ten adult male wild-type and 12 CDKL5-knockout mice underwent electrode implantation for sleep stage discrimination and diaphragmatic activity recording, and were studied using whole-body plethysmography for 7 hr during the light (resting) period. Sleep apneas were categorised as central sleep apnea or obstructive sleep apnea based on the recorded signals. The number of somatostatin neurons in the preBötzinger complex and their neurokinin-1 receptors expression were assessed through immunohistochemistry in a sub-group of animals. CDKL5-knockout mice exhibited a higher apnea occurrence rate and a greater prevalence of obstructive sleep apnea during rapid eye movement sleep, compared with wild-type, whereas no significant difference was observed for central sleep apnea. Moreover, CDKL5-knockout mice showed a reduced number of somatostatin neurons in the preBötzinger complex, and these neurons expressed a lower level of neurokinin-1 receptors compared with wild-type controls. These findings underscore the pivotal role of CDKL5 in regulating normal breathing, suggesting its potential involvement in shaping preBötzinger complex neural circuitry and controlling respiratory muscles during sleep.
CDKL5缺乏症是一种由CDKL5基因突变引起的罕见遗传病。据报道，患有CDKL5缺乏症的患者在清醒时会出现中枢性呼吸暂停。对CDKL5基因敲除小鼠（一种CDKL5缺乏症模型）的研究报告了睡眠呼吸暂停，但目前尚不清楚这些事件是中枢性的（中枢性睡眠呼吸暂停）还是阻塞性的（阻塞性睡眠呼吸暂停），并且可能与调节呼吸节律的脑回路改变有关。本研究旨在区分CDKL5基因敲除小鼠的中枢性睡眠呼吸暂停和阻塞性睡眠呼吸暂停，并探索前包钦格复合体中表达高水平神经激肽-1受体的生长抑素神经元的变化。对10只成年雄性野生型小鼠和12只CDKL5基因敲除小鼠进行电极植入，以区分睡眠阶段并记录膈肌活动，并在光照（休息）期间使用全身体积描记法进行7小时的研究。根据记录的信号将睡眠呼吸暂停分类为中枢性睡眠呼吸暂停或阻塞性睡眠呼吸暂停。通过免疫组织化学对一组动物评估前包钦格复合体中生长抑素神经元的数量及其神经激肽-1受体的表达。与野生型小鼠相比，CDKL5基因敲除小鼠在快速眼动睡眠期间表现出更高的呼吸暂停发生率和更高的阻塞性睡眠呼吸暂停患病率，而中枢性睡眠呼吸暂停则未观察到显著差异。此外，与野生型对照相比，CDKL5基因敲除小鼠在前包钦格复合体中的生长抑素神经元数量减少，并且这些神经元表达的神经激肽-1受体水平较低。这些发现强调了CDKL5在调节正常呼吸中的关键作用，表明其可能参与塑造前包钦格复合体神经回路并在睡眠期间控制呼吸肌。
