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Review

Autism, fever, epigenetics and the locus coeruleus

Mark F. Mehlera,b,c,d,e,f,g,⁎, Dominick P. Purpuraa,d,f

aInstitute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine,1410 Pelham Parkway South, Bronx, New York 10461, USAbRoslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine,1410 Pelham Parkway South, Bronx, New York 10461, USAcThe Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USAdDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South,Bronx, New York 10461, USAeDepartment of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine,1410 Pelham Parkway South, Bronx, New York 10461, USAfRose F. Kennedy Center for Research in Intellectual and Developmental Disabilities, Albert Einstein College of Medicine,1410 Pelham Parkway South, Bronx, New York 10461, USAgEinstein Cancer Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USA

A R T I C L E I N F O

⁎ Corresponding author. The Saul R. Korey DBronx, New York 10461, USA.

LC-NA, locus coeruleus-noradrenergic system

0165-0173/$ – see front matter © 2008 Elsevidoi:10.1016/j.brainresrev.2008.11.001

A B S T R A C T

Article history:Accepted 18 November 2008Available online 24 November 2008

Some children with autism spectrum disorders (ASD) exhibit improved behaviors andenhanced communication during febrile episodes. We hypothesize that febrigenesis andthe behavioral-state changes associated with fever in autism depend upon selectivenormalization of key components of a functionally impaired locus coeruleus-noradrenergic(LC-NA) system. We posit that autistic behaviors result from developmental dysregulationof LC-NA system specification and neural network deployment and modulation linked tothe core behavioral features of autism. Fever transiently restores the modulatory functionsof the LC-NA system and ameliorates autistic behaviors. Fever-induced reversibility ofautism suggests preserved functional integrity of widespread neural networks subservingthe LC-NA system and specifically the subsystems involved in mediating the cognitive andbehavioral repertoires compromised in ASD. Alterations of complex gene–environmentalinteractions and associated epigenetic mechanisms during seminal developmental criticalperiods are viewed as instrumental in LC-NA dysregulation as emphasized by the timingand severity of prenatal maternal stressors on autism prevalence. Our hypothesis hasimplications for a rational approach to further interrogate the interdisciplinary etiology ofASD and for designing novel biological detection systems and therapeutic agents that targetthe LC-NA system's diverse network of pre- and postsynaptic receptors, intracellularsignaling pathways and dynamic epigenetic remodeling processes involved in theirregulation and functional plasticity.

© 2008 Elsevier B.V. All rights reserved.

Keywords:Gene–environmental interactionPrenatal stressorNeuromodulatorSensorimotor processingHomeostatic signalDevelopmental critical periodImprinted genePharmacoepigenomic agent

epartment of Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway South,

E-mail address: mehler@aecom.yu.edu (M.F. Mehler).Abbreviations: ASD, autism spectrum disorders; CpG, cytosine dinucleotide; CRH, corticotropin-releasing hormone; LC, locus coeruleus;

; LPS, lipopolysaccharide; NA, noradrenaline

er B.V. All rights reserved.

389B R A I N R E S E A R C H R E V I E W S 5 9 ( 2 0 0 9 ) 3 8 8 – 3 9 2

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3892. The locus coeruleus-noradrenergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3893. Fever, neural network plasticity and the locus coeruleus system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3904. Autism-related developmental and epigenetic dysregulation of the locus coeruleus-noradrenergic system . . . . . . . . 3905. Developmental stress, epigenetic modulation and potentially reversible locus coeruleus-noradrenergic system

dysregulation in ASD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3906. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

1. Introduction

Autism spectrum disorders (ASD) are heritable developmentaldisorders characterized by impairments in social interaction,language and communication deficits and repetitive or stereo-typed behaviors. Although the genetic contributions to ASD arebeing intensively explored (Abrahams and Geschwind, 2008;Morrow et al., 2008; Sebat et al., 2007), little is known concerningthe relationship of genetic, epigenetic and environmental factorsto the core features or neuropathological substrate underlyingASD (Persico and Bourgeron, 2006). We believe the neurobiologyof autism may be informed by parent reports, clinical observa-tions and formal studies indicating that autistic behaviors areameliorated in some children during febrile episodes (Curran etal., 2007). The association of fever and behavioral improvementin ASD provides clues to the pathophysiology of autisticbehaviors and to potential therapeutic interventions. Accord-ingly,weposit that thedramatic fluctuations in behavioral statesoccurring during febrile episodes suggest the involvement of apervasive neural system that can effect relatively rapid changesin the functionalactivityofwidespreadneuralnetworks involvedin the core features of ASD. The locus coeruleus-noradrenergicsystem (LC-NA) represents such a widespread and versatileneuromodulatory system that we suggest is common tofebrigenesis and the modulation of autistic behaviors. Wehypothesize that intrinsic and environmental stressors actingupon a substrate of genetic and epigenetic variations during aprotracted maturational window of vulnerability developmen-tally dysregulate the LC-NA system. Febrile episodes ameliorateautistic behaviors bydifferentiallymodulating theLC-NAsystemand transiently restoring the functional integrity of its distrib-uted neural networks primarily involved in mediating socialcommunication, complex motor programs and instrumentalbehaviors. Several lines of evidence support this hypothesis.

2. The locus coeruleus-noradrenergic system

The locus coeruleus is a small-pigmented nucleus nestled inthe rostral dorsolateral pontine tegmentum. The LC inhumans consists of approximately 40,000 neurons with themost widespread efferent projections of any neurons in thebrain (Foote et al., 1983). All of the noradrenaline (NA) in thecerebral cortex and hippocampus and most of the NA in otherparts of the neuraxis including the cerebellum is produced and

transported by LC neurons in axons with hundreds ofthousands of NA-containing varicosities (Oleskevich et al.,1989). By virtue of their complex but selective patterns ofinnervation within and across different forebrain structures,LC-NA neurons gain access to a diverse but targeted array ofinteracting neural networks. For example, there are sugges-tions that preferential noradrenergic innervation of selectivecomponents of the visual system promotes more global visualspatial analysis and elaboration of visuomotor responses asopposed to a greater focus on stimulus feature extraction andpattern analysis, consistent with the visual sensory domainsmost impaired in autism (Berridge and Waterhouse, 2003).Such networks can be influenced through actions at multiplestages of sensorimotor processing, and by activating distinctintracellular signaling cascades that permit elaboration of adynamic range of neuronal response properties and rapidreorganization of relevant neural networks for efficient andflexible behavioral adaptations (Berridge and Waterhouse,2003). The widespread efferent projections of the LC areparalleled by equally diverse afferent projections to LC neuroncell bodies and their dendritic systems (Van Bockstaele et al.,2001). These arise from brainstem catecholamine- and ser-otonin-containing nuclei that provide homeostatic inputs tomodulate LC-NA output properties as well as afferents fromthe cerebral cortex, amygdala, basal forebrain and hypothala-mus that provide integrated feedback modulation based onevolving environmental contingencies. There is also evidencefor separate corticotropin-releasing hormone (CRH) inputs tothe locus coeruleus that specifically modulate noradrenergicneuronal activation by physiological and environmentalstressors (Van Bockstaele et al., 2001).

Earlier views of the preeminent role of the LC-NA system inarousal and attention have been greatly expanded to includeinvolvement of the LC-NA system in virtually all aspects ofbehavioral adaptations and performance with particularrelevance to integrative cognitive domains disproportionatelyaffected in ASD: exploration within a complex and dynamicenvironment and the acquisition, retention,manipulation andutilization of salient environmental cues (Aston-Jones andCohen, 2005; Van Bockstaele et al., 2001). A proposal ofparticular merit analogizes the operation of the LC-NA systemin mammals with the neuromodulatory function of neuronsthat regulate ‘flips’ in complex behavior patterns in inverte-brates (Bouret and Sara, 2005). The organizing principle thatemerges from recent research is that distributed neuralnetworks, such as those involved in cognitively demanding

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tasks (Sridharan et al., 2008), are under modulatory control bythe LC-NA system and associated homeostatic signals includ-ing circadian rhythms to facilitate rapid and widespreadneural network remodeling to promote behavioral adaptationsto environmental imperatives. It is therefore not surprisingthat the LC-NA system has been implicated in the etiology ofpost-traumatic stress disorders, neurodegenerative diseases,schizophrenia, depression and other psychiatric conditions(Aston-Jones and Cohen, 2005; Berridge, 2008; Van Bockstaeleet al., 2001). The role of the LC-NA system in autism hasescaped attention until now as we seek a parsimoniousexplanation for the association of febrile episodes andimprovement in autistic behaviors.

3. Fever, neural networkplasticity and the locuscoeruleus system

What is the evidence that febrigenesis involves the LC-NAsystem? Bacterial lipopolysaccharide (LPS)-induced fever acti-vates preoptic area noradrenergic terminals (Linthorst et al.,1995) and chemical lesions of NA-containing afferents to theparaventricular nucleus inhibit the fever response to inter-leukin-1 (Ovadia et al., 1989). While it is now well establishedthat preoptic NA mediates LPS-induced fever (Feleder et al.,2007), the NA neurons involved in fever have only recentlybeen elucidated in findings that electrolytic and chemicallesions of LC markedly attenuate LPS-induced fever inlaboratory animals (Almeida et al., 2004). Thus LC-NA-hypothalamic pathways activated by febrigenic stimuli alterthe excitatory state of LC-NA neurons during fever. Since LCneurons exhibit highly synchronized activity attributable todendritic electrical interactions, activation of a subpopulationof LC neurons projecting to the hypothalamus could readilyspread throughout the nucleus, causing functional remodelingand altered neuronal response properties of differentialcomponents of the entire LC-NA system. (Steininger et al.,2001) Altered LC-NAneural network deployment and neuronalactivation, we infer, is the restorative event in the transientamelioration of autistic behaviors during fever. This hypoth-esis is in keeping with studies that have failed to findsubstantive neuropathological lesions in the cerebral cortexand other brain sites (Amaral et al., 2008), and reports of thepaucity of associated anatomical abnormalities in the LC inASD (Hashemi et al., 2007; Martchek et al., 2006). Early buttransient brain overgrowth has been reported in ASD (Courch-esne et al., 2007), and this suggests that dynamic develop-mental dysregulation is occurring through complex gene–environmental interactions (see below). We argue that insofaras ASD is a heterogeneous disorder in which waxing andwaning of autistic behaviors occur during fever and deferves-cence and also during specific developmental epochs, theneural networks responsible for ASD, particularly in higherfunctioning patients, should be functionally intact. This hasimplications for a rational pharmacotherapy of autism thattargets the LC-NA systemand its diverse pre- and postsynapticreceptors. Although favorable responses to some alpha-adrenergic agonists have been reported in ASD (Erickson etal., 2007), the diversity of neurochemical, developmental andepigenetic regulatory systems associated with the LC-NA

system (see below) suggest that more diverse, selective,versatile and novel therapeutic targets and pharmacoepige-nomic agents will soon emerge.

4. Autism-relateddevelopmental and epigeneticdysregulation of the locus coeruleus-noradrenergicsystem

There remains to consider the events and processes that couldlead to developmental dysregulation of the LC-NA system andASD (Cheslack-Postava et al., 2007; Connors et al., 2005).Intricate profiles of developmental cues are elaborated duringprogressive developmental critical periods to ensure thefidelity of the specification, deployment and refinement ofthe emerging LC-NA system (Hashemi et al., 2007; Holm et al.,2006). A significant subset of these interacting developmentalgenes and gene networks has been implicated in ASD(Abrahams andGeschwind, 2008;Morrowet al., 2008; Schanen,2006). LC-NAdevelopmental genes are under exquisite degreesof epigenetic regulation, suggesting the influence of complexgene–environmental interactions and high degrees of con-textual control (Hashemi et al., 2007; Holm et al., 2006; Persicoand Bourgeron, 2006; Schanen, 2006). These observations areconsistent with emerging observations suggesting the dysre-gulation of multiple epigenetic regulatory processes in ASD(Persico and Bourgeron, 2006; Schanen, 2006). These includemultiple imprinted loci implicated in ASD and encompassingcomplex genomic regulatory regions under the control ofmultiple diverse epigenetic processes and involved in orches-trating numerous seminal brain maturational and plasticityprocesses that are selectively dysregulated in ASD (Badcockand Crespi, 2006; Mehler and Mattick, 2007; Schanen, 2006).Interestingly, there are specific imprinted genes involved inLC-NA deployment and in mediating behavioral responses tonovel environmental conditions (Plagge et al., 2005). ASD-associated epigenetic alterations in the fidelity of regionalpatterning, specification andprogressivematurationof the LC-NA system would result in a complex amalgam of corebehavioral deficits and a spectrum of clinical severity depend-ing on the profile of maturational deficits associated withepigenetic dysregulation of specific developmental criticalperiods (Aston-Jones and Cohen, 2005; Berridge and Water-house, 2003; Bouret and Sara, 2005; Hashemi et al., 2007; Holmet al., 2006; Persico and Bourgeron, 2006; Schanen, 2006).

5. Developmental stress, epigeneticmodulation and potentially reversible locuscoeruleus-noradrenergic system dysregulationin ASD

Prenatal stressors, appropriately timed and sufficientlyintense, could also be important in dysregulating the LC-NAsystem. In view of the metabolic load LC neurons bear insupporting vast axonal networks with millions of NA ladenvesicles, we suspect that they might be selectively vulnerableto stress-induced functional dysregulation. Prenatal stressfulevents are reported more frequently in mothers of autisticchildren than mothers of control children (Beversdorf et al.,

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2005). Natural disasters are compelling in this respect. Thesehave revealed a significant increase in autism prevalencefollowing maternal exposure to hurricanes and tropicalstorms over a 15-year period in Louisiana (Kinney et al.,2008). A dose-response effect was related to the severity ofstorm exposure. Interestingly, maternal exposure to severestorms at mid-gestation resulted in the highest prevalence ofautism in affected cohorts.

To the extent that high levels of maternal stress-inducedcortisolmight affect fetal LC-NA regulation, it is of interest that atmid-gestation the catalytic enzyme that inactivates cortisol, 11β-hydroxysteroid dehydrogenase-2, is downregulated in the pla-centa, thereby enhancing transplacental transport of the stresshormone into the fetal brain (Holmes et al., 2006). In addition,during this critical period for progressive phases of locuscoeruleus development, 11 β-hydroxysteroid dehydrogenase-2is under dynamic and potentially dysregulated epigeneticmodulation through the actions of differential promoter cytosinedinucleotide (CpG) island methylation, methyl CpG-bindingproteins and specific transcriptional regulators associated withASD (Abrahams and Geschwind, 2008; Alikhani-Koopaei et al.,2004). These intrauterine perturbations can significantly alter thenormal neuronal and regional noradrenergic receptor subunitcomplement, electrotonic coupling and associated early attach-ment learning and environmental discrimination (Moriceau andSullivan, 2005). Interestingly, Crh gene expression is elevated in aRett syndrome (MeCP2 mutant) mouse model and is associatedwith abnormal stress responses (McGill et al., 2006). MeCP2 isknown to bind the Crh promoter that is normally enriched inmethylated CpG dinucleotides, and exogenous NA administra-tion ameliorates the abnormal neural response networksobserved in MeCP2 mutant mice (McGill et al., 2006; Viemari etal., 2005). These observations suggest that in addition to intrinsicepigenetically mediated ASD developmental abnormalitiesoccurring during progressive stages of locus coeruleus develop-ment, there are concurrent and continuing epigenetically depen-dent environmental stressors that have the potential to furthercompromise the functional integrity of LC-NA neural networks.

6. Conclusions

The importance of our hypothesis, apart from its ability toexplain widely divergent and complex features of ASD,including the ‘fever effect’, lies in its promise for the develop-ment of innovative diagnostic and therapeutic approaches toautism. We anticipate that the design of advanced moleculargenetic platforms and functional neuroimaging paradigms forpre-clinical disease detection and the identification of earlybiomarkers will permit the analysis of disease progression andresponses to pharmacologic and behavioral interventions.Additionally, generation of more relevant and robust animalmodels of autism will help to elucidate novel classes oftherapeutic agents that target the evolving LC-NA systemand its mature and widely distributed but selective neuralnetworks, signaling pathways and epigenetic modifiers ofnetwork plasticity and connectivity. Recent studies emphasizethe potential power of evolving molecular genetic as well asnewer pharmacoepigenomic therapies to promote “recovery”of seemingly irrevocably lost long-termmemories and higher-

order cognitive and behavioral functions and even “rejuvena-tion” of dyingneurons in advanced cases of neurodegenerativediseases (Chan et al., 2007; Fischer et al., 2007). Thuscomplementary therapeutic approaches organized within thecontext of translational research initiatives in developmentalneuroscience, epigenomic medicine, systems biology andmaternal and environmental health will allow for perma-nent reversal of the higher-order cognitive and behavioraldeficits observed in ASD and perhaps in other pervasive andpresently intractable neuropsychiatric disorders.

Acknowledgments

This work was supported in part by the National Institutes ofHealth grants RO1MH66290 and RO1 NS38902 and grants fromthe 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.).

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