Perez-Ternero Cristina, Pallier Patrick N, Tremoleda Jordi L, Delogu Alessio, Fernandes Cathy, Michael-Titus Adina T, Hobbs Adrian J
William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Front Mol Neurosci. 2022 Oct 4;15:991112. doi: 10.3389/fnmol.2022.991112. eCollection 2022.
C-type natriuretic peptide (CNP) is highly expressed in the central nervous system (CNS) and key to neuronal development; however, a broader role for CNP in the CNS remains unclear. To address this deficit, we investigated behavioral, sensory and motor abnormalities and blood-brain barrier (BBB) integrity in a unique mouse model with inducible, global deletion of CNP (gbCNP). gbCNP mice and wild-type littermates at 12 (young adult) and 65 (aged) weeks of age were investigated for changes in gait and motor coordination (CatWalk and rotarod tests), anxiety-like behavior (open field and elevated zero maze tests), and motor and sensory function (modified neurological severity score [mNSS] and primary SHIRPA screen). Vascular permeability was assessed (Miles assay) with complementary studies conducted in primary murine brain endothelial cells. Young adult gbCNP mice had normal gait but reduced motor coordination, increased locomotor activity in the open field and elevated zero maze, and had a higher mNSS score. Aged gbCNP animals developed recurrent spontaneous seizures and had impaired gait and wide-ranging motor and sensory dysfunction. Young adult and aged gbCNP mice exhibited increased BBB permeability, which was partially restored by CNP administration. Cultured brain endothelial cells from gbCNP mice had an abnormal ZO-1 protein distribution. These data suggest that lack of CNP in the CNS impairs tight junction protein arrangement and increases BBB permeability, which is associated with changes in locomotor activity, motor coordination and late-onset seizures.
C型利钠肽（CNP）在中枢神经系统（CNS）中高度表达，对神经元发育至关重要；然而，CNP在中枢神经系统中更广泛的作用仍不清楚。为了解决这一不足，我们在一种独特的可诱导全身性缺失CNP（gbCNP）的小鼠模型中，研究了行为、感觉和运动异常以及血脑屏障（BBB）的完整性。对12周龄（年轻成年）和65周龄（老年）的gbCNP小鼠及野生型同窝小鼠进行了步态和运动协调性变化（CatWalk和转棒试验）、焦虑样行为（旷场试验和高架零迷宫试验）以及运动和感觉功能（改良神经功能严重程度评分[mNSS]和初级SHIRPA筛查）的研究。通过在原代小鼠脑内皮细胞中进行的补充研究评估血管通透性（迈尔斯试验）。年轻成年gbCNP小鼠步态正常，但运动协调性降低，在旷场试验和高架零迷宫试验中的自发活动增加，且mNSS评分更高。老年gbCNP动物出现反复自发性癫痫发作，步态受损，运动和感觉功能广泛受损。年轻成年和老年gbCNP小鼠均表现出血脑屏障通透性增加，给予CNP后可部分恢复。来自gbCNP小鼠的培养脑内皮细胞中ZO-1蛋白分布异常。这些数据表明，中枢神经系统中缺乏CNP会损害紧密连接蛋白的排列，增加血脑屏障通透性，这与自发活动、运动协调性变化和迟发性癫痫发作有关。
