Autism, fever, epigenetics and the locus coeruleus.
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.
Mehler
Mark F
MF
Institute for Brain Disorders and Neural Regeneration, The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. mehler@aecom.yu.edu
Purpura
Dominick P
DP
D000818:Animals; D001321:Autistic Disorder / Q000209:etiology / Q000503:physiopathology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D005334:Fever / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008125:Locus Coeruleus / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D009415:Nerve Net / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism / Q000503:physiopathology