Coq Jacques-Olivier, Delcour Maxime, Ogawa Yuko, Peyronnet Julie, Castets Francis, Turle-Lorenzo Nathalie, Montel Valérie, Bodineau Laurence, Cardot Phillipe, Brocard Cécile, Liabeuf Sylvie, Bastide Bruno, Canu Marie-Hélène, Tsuji Masahiro, Cayetanot Florence
Centre National de la Recherche Scientifique, Institut de Neurosciences de la Timone, UMR 7289, Aix Marseille Université, Marseille, France.
Centre National de la Recherche Scientifique, Neurosciences Intégratives et Adaptatives, UMR 7260, Aix Marseille Université, Marseille, France.
Front Neurol. 2018 Jun 15;9:423. doi: 10.3389/fneur.2018.00423. eCollection 2018.
Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.
宫内缺血缺氧对发育中的大脑有害，会导致白质损伤（WMI）、早产儿脑病（EP），并常常引发脑瘫（CP），但其相关的病理生理机制仍不清楚。在先前的研究中，我们在大鼠中使用轻度宫内低灌注（MIUH）成功再现了EP的临床症状多样性以及一些CP症状。简而言之，MIUH导致炎症反应、弥漫性灰质和白质损伤、轻微运动功能缺陷、肌肉骨骼病变、初级体感和运动皮层的神经解剖和功能紊乱、感觉运动反射延迟、自发多动、感觉信息处理缺陷、记忆和学习障碍。在本研究中，我们调查了可能导致MIUH诱导的各种症状的早期和长期病理生理机制。我们发现早期反射亢进、痉挛以及KCC2（一种调节氯离子稳态和细胞兴奋性的氯共转运体）表达降低。成年MIUH大鼠表现出肌肉收缩特性和表型的变化、持续性反射亢进和痉挛，以及感觉运动皮层的兴奋性过高。综上所述，这些结果表明KCC2表达降低、腰部反射亢进、痉挛、比目鱼肌特性改变以及皮层兴奋性过高可能相互作用形成一个自我持续的循环，导致EP和CP中神经发育障碍（NDD）的出现和持续存在，如感觉运动障碍，以及可能的多动、注意力和学习障碍。
