ReviewAutism, fever, epigenetics and the locus coeruleus
Introduction
Autism spectrum disorders (ASD) are heritable developmental disorders characterized by impairments in social interaction, language and communication deficits and repetitive or stereotyped behaviors. Although the genetic contributions to ASD are being intensively explored (Abrahams and Geschwind, 2008, Morrow et al., 2008, Sebat et al., 2007), little is known concerning the relationship of genetic, epigenetic and environmental factors to the core features or neuropathological substrate underlying ASD (Persico and Bourgeron, 2006). We believe the neurobiology of autism may be informed by parent reports, clinical observations and formal studies indicating that autistic behaviors are ameliorated in some children during febrile episodes (Curran et al., 2007). The association of fever and behavioral improvement in ASD provides clues to the pathophysiology of autistic behaviors and to potential therapeutic interventions. Accordingly, we posit that the dramatic fluctuations in behavioral states occurring during febrile episodes suggest the involvement of a pervasive neural system that can effect relatively rapid changes in the functional activity of widespread neural networks involved in the core features of ASD. The locus coeruleus-noradrenergic system (LC-NA) represents such a widespread and versatile neuromodulatory system that we suggest is common to febrigenesis and the modulation of autistic behaviors. We hypothesize that intrinsic and environmental stressors acting upon a substrate of genetic and epigenetic variations during a protracted maturational window of vulnerability developmentally dysregulate the LC-NA system. Febrile episodes ameliorate autistic behaviors by differentially modulating the LC-NA system and transiently restoring the functional integrity of its distributed neural networks primarily involved in mediating social communication, complex motor programs and instrumental behaviors. Several lines of evidence support this hypothesis.
Section snippets
The locus coeruleus-noradrenergic system
The locus coeruleus is a small-pigmented nucleus nestled in the rostral dorsolateral pontine tegmentum. The LC in humans consists of approximately 40,000 neurons with the most widespread efferent projections of any neurons in the brain (Foote et al., 1983). All of the noradrenaline (NA) in the cerebral cortex and hippocampus and most of the NA in other parts of the neuraxis including the cerebellum is produced and transported by LC neurons in axons with hundreds of thousands of NA-containing
Fever, neural network plasticity and the locus coeruleus system
What is the evidence that febrigenesis involves the LC-NA system? Bacterial lipopolysaccharide (LPS)-induced fever activates preoptic area noradrenergic terminals (Linthorst et al., 1995) and chemical lesions of NA-containing afferents to the paraventricular nucleus inhibit the fever response to interleukin-1 (Ovadia et al., 1989). While it is now well established that preoptic NA mediates LPS-induced fever (Feleder et al., 2007), the NA neurons involved in fever have only recently been
Autism-related developmental and epigenetic dysregulation of the locus coeruleus-noradrenergic system
There remains to consider the events and processes that could lead to developmental dysregulation of the LC-NA system and ASD (Cheslack-Postava et al., 2007, Connors et al., 2005). Intricate profiles of developmental cues are elaborated during progressive developmental critical periods to ensure the fidelity of the specification, deployment and refinement of the emerging LC-NA system (Hashemi et al., 2007, Holm et al., 2006). A significant subset of these interacting developmental genes and
Developmental stress, epigenetic modulation and potentially reversible locus coeruleus-noradrenergic system dysregulation in ASD
Prenatal stressors, appropriately timed and sufficiently intense, could also be important in dysregulating the LC-NA system. In view of the metabolic load LC neurons bear in supporting vast axonal networks with millions of NA laden vesicles, we suspect that they might be selectively vulnerable to stress-induced functional dysregulation. Prenatal stressful events are reported more frequently in mothers of autistic children than mothers of control children (Beversdorf et al., 2005). Natural
Conclusions
The importance of our hypothesis, apart from its ability to explain widely divergent and complex features of ASD, including the ‘fever effect’, lies in its promise for the development of innovative diagnostic and therapeutic approaches to autism. We anticipate that the design of advanced molecular genetic platforms and functional neuroimaging paradigms for pre-clinical disease detection and the identification of early biomarkers will permit the analysis of disease progression and responses to
Acknowledgments
This work was supported in part by the National Institutes of Health grants RO1 MH66290 and RO1 NS38902 and grants from the Roslyn and Leslie Goldstein, the Mildred and Bernard H. Kayden, the F. M. Kirby, the Alpern Family and the Rosanne H. Silberman Foundations (M. F. M.).
References (39)
- et al.
Neuroanatomy of autism
Trends Neurosci.
(2008) Noradrenergic modulation of arousal
Brain Res. Rev.
(2008)- et al.
The locus coeruleus-noradrenergic system. modulation of behavioral state and state-dependent cognitive processes
Brain Res. Brain Res. Rev.
(2003) - et al.
Network reset: a simplified overarching theory of locus coeruleus noradrenaline function
Trends Neurosci.
(2005) - et al.
Mapping early brain development in autism
Neuron
(2007) - et al.
Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites
Brain Res.
(2007) - et al.
Evidence for the involvement of the central adrenergic system in the febrile response induced by interleukin-1 in rats
J. Neuroimmunol.
(1989) - et al.
Searching for ways out of the autism maze: genetic, epigenetic and environmental clues
Trends Neurosci.
(2006) - et al.
Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus
Physiol. Behav.
(2001) - et al.
Advances in autism genetics: on the threshold of a new neurobiology
Nat. Rev., Genet.
(2008)
Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression
J. Clin. Invest.
Thermoeffector neuronal pathways in fever: a study in rats showing a new role of the locus coeruleus
J. Physiol.
An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance
Annu. Rev. Neurosci.
Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism
J. Evol. Biol.
Timing of prenatal stressors and autism
J. Autism. Dev. Disord.
‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease
Nature
Beta2-adrenergic receptor gene variants and risk for autism in the AGRE cohort
Mol. Psychiatry
Beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins
J. Child Neurol.
Behaviors associated with fever in children with autism spectrum disorders
Pediatrics
Cited by (90)
Environmental Influence on Epigenetics
2022, Handbook of Epigenetics: The New Molecular and Medical Genetics, Third EditionErbB4 regulate extracellular dopamine through the p38 MAPK signaling pathway
2021, Neuroscience LettersDominick P. Purpura
2021, Child Neurology: Its Origins, Founders, Growth and EvolutionAnxiety: An ignored aspect of Parkinson's disease lacking attention
2020, Biomedicine and PharmacotherapyThe Role of the Noradrenergic System in Autism Spectrum Disorders, Implications for Treatment
2020, Seminars in Pediatric NeurologyCitation Excerpt :Furthermore, pathology is not found in the volume, cell counts, or cell density in postmortem tissue from the locus coeruleus in ASD.74 Others, though, have proposed that the behavioral effects of fever in ASD75 may be related to normalization of a developmentally dysregulated noradrenergic system.76 While the nature of neuropathological changes of the noradrenergic system in ASD remain a question, there are a number of other lines of evidence that at least support autonomic dysregulation.
Oxytocin release via activation of TRPM2 and CD38 in the hypothalamus during hyperthermia in mice: Implication for autism spectrum disorder
2018, Neurochemistry InternationalCitation Excerpt :Some autistic children exhibit improvements in their characteristic autistic behaviors during febrile incidents, and the regression of fever may be associated with the onset of ASD (Megremi, 2013; Good, 2011; Curran et al., 2007; Naviaux et al., 2015, 2017; Mehler and Purpura, 2009). Febrigenesis and the behavioral state changes associated with fever in ASD depend on the selective normalization of key components in a functionally impaired locus coeruleus-noradrenergic system (Mehler and Purpura, 2009). The report by Zhong et al. (2016) presented for the first time a new neuroendocrinological idea that fever may enhance the release of OT to reduce abnormal autistic behavior because external administration of OT was shown to improve aberrant behavior in rodents and in humans (Figs. 3 and 5) (Jin et al., 2007; Munesue et al., 2010, 2016; Yatawara et al., 2016; Watanabe et al., 2015; Kosaka et al., 2016).