Mehler Mark F, Purpura Dominick P
Institute for Brain Disorders and Neural Regeneration, The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Brain Res Rev. 2009 Mar;59(2):388-92. doi: 10.1016/j.brainresrev.2008.11.001. Epub 2008 Nov 24.
Some children with autism spectrum disorders (ASD) exhibit improved behaviors and enhanced communication during febrile episodes. We hypothesize that febrigenesis and the behavioral-state changes associated with fever in autism depend upon selective normalization of key components of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system. We posit that autistic behaviors result from developmental dysregulation of LC-NA system specification and neural network deployment and modulation linked to the core behavioral features of autism. Fever transiently restores the modulatory functions of the LC-NA system and ameliorates autistic behaviors. Fever-induced reversibility of autism suggests preserved functional integrity of widespread neural networks subserving the LC-NA system and specifically the subsystems involved in mediating the cognitive and behavioral repertoires compromised in ASD. Alterations of complex gene-environmental interactions and associated epigenetic mechanisms during seminal developmental critical periods are viewed as instrumental in LC-NA dysregulation as emphasized by the timing and severity of prenatal maternal stressors on autism prevalence. Our hypothesis has implications for a rational approach to further interrogate the interdisciplinary etiology of ASD and for designing novel biological detection systems and therapeutic agents that target the LC-NA system's diverse network of pre- and postsynaptic receptors, intracellular signaling pathways and dynamic epigenetic remodeling processes involved in their regulation and functional plasticity.
一些患有自闭症谱系障碍（ASD）的儿童在发热期间表现出行为改善和沟通能力增强。我们假设，自闭症患者发热的产生以及与发热相关的行为状态变化取决于功能受损的蓝斑-去甲肾上腺素能（LC-NA）系统关键成分的选择性正常化。我们认为，自闭症行为是由LC-NA系统规范以及与自闭症核心行为特征相关的神经网络部署和调制的发育失调所导致的。发热可暂时恢复LC-NA系统的调节功能并改善自闭症行为。发热引起的自闭症可逆性表明，广泛的神经网络保持了功能完整性，这些神经网络支持LC-NA系统，特别是参与介导ASD中受损的认知和行为表现的子系统。在关键发育时期，复杂的基因-环境相互作用以及相关的表观遗传机制的改变被认为在LC-NA失调中起作用，产前母体应激源对自闭症患病率的时间和严重程度就强调了这一点。我们的假设对于进一步探究ASD跨学科病因的合理方法，以及设计针对LC-NA系统突触前和突触后受体、细胞内信号通路以及参与其调节和功能可塑性的动态表观遗传重塑过程的新型生物检测系统和治疗药物具有重要意义。
