Skip to content

Advertisement

Molecular Autism

Review
Open Access

From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition

  • Adam M. H. Young1, 2Email author,
  • Bhismadev Chakrabarti1, 3,
  • David Roberts2,
  • Meng-Chuan Lai1, 4, 5,
  • John Suckling6, 7 and
  • Simon Baron-Cohen1, 8
Molecular AutismBrain, Cognition and Behavior20167:9

https://doi.org/10.1186/s13229-016-0068-x

©  Young et al. 2016

Received: 25 September 2014

Accepted: 4 January 2016

Published: 20 January 2016

Abstract

Growing evidence points toward a critical role for early (prenatal) atypical neurodevelopmental processes in the aetiology of autism spectrum condition (ASC). One such process that could impact early neural development is inflammation. We review the evidence for atypical expression of molecular markers in the amniotic fluid, serum, cerebrospinal fluid (CSF), and the brain parenchyma that suggest a role for inflammation in the emergence of ASC. This is complemented with a number of neuroimaging and neuropathological studies describing microglial activation. Implications for treatment are discussed.

Keywords

NF-κBAutismBrainInflammation

Background

The presence of inflammation in autism spectrum condition (ASC) is a concept that is gathering momentum. Traditionally, different forms of ASC have been recognised: Classic (or Kanner type) autism (which can entail general intellectual disability and language delay), Asperger syndrome (which entails no developmental language delay or intellectual disability) and syndromic forms of autism such as co-occurring with Rett syndrome, Fragile X syndrome, tuberous sclerosis complex and Timothy’s syndrome, to name a few [29]. In DSM-5, these are now subsumed under a single umbrella term of autism spectrum disorder (ASD). In this article, we use the term autism spectrum condition (ASC) because the term ‘disorder’ is regarded by some as stigmatising and the term ‘condition’ acknowledges both the disability and the differences and strengths in such individuals.

The key behavioural features defining ASC are the presence of difficulties in social reciprocity and communication, alongside unusually narrow interests, repetitive behaviours and speech, insistence on sameness, and idiosyncratic sensory responses DSM-V® [30]. Cognitively, ASC is described as a condition characterised by weakened central coherence [35, 46], executive dysfunction [76], and mentalising difficulties [5, 6] alongside strengths in ‘systemizing’ [5] and attention to detail [82, 83]. Genetic, environmental, neurological, and immunological factors contribute to its aetiology [72].

Some, but not all, studies suggest that ASC involves early brain overgrowth [21, 74]. This is unlikely to be a universal phenomenon [17, 73] and is one of the key factors that could be linked to the heterogeneity of the condition together with neuroinflammation. Nevertheless, there are a multitude of developmental reasons which could be responsible for this observation, including atypical pruning of synapses [41] and, more recently, neuron density has been shown to play a significant role [22], but this could also reflect neuroinflammation. Animal models have identified microglial priming as a major factor in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes [59]. Increased head size in people with ASC correlates positively with a history of allergic/immune disorders [86]. In particular, there is an association between ASC and neuroinflammation in anterior regions of the neocortex [79, 101, 110], resulting from activation of microglia and astrocytes [2]. Gene networks involved in immune processes are overexpressed in the brain of individuals with ASC [102, 103]. This has been linked to atypical expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in a number of cell types in ASC including neurons, astrocytes, and microglia [107]. This has a linear relationship with pH changes localised to the lysosomal compartments of mature microglia [107], indicating increased immune activity. Microglia play a critical role in the pruning of synapses, thus providing a potential bridge between the atypical synaptic pruning and the immune dysregulatory hypotheses of ASC [78]. Below we review the mechanisms that may underlie neuroinflammation and the evidence at genetic and protein levels for each of these mechanisms (Table 1).
Table 1

Summary of contributing immunological factors in ASC

Level of biological processes

Immunological factors involved

Genetic

IFN-γ, Toll-like receptors, T-cell receptor

Extracellular mediators

Maternal antibodies, cytokines and chemokines

Cell surface proteins

Human leukocyte antigen, Toll-like receptors

Intracellular signalling

mTOR, PTEN, NF-κB

Neural changes

Neuron density, glial proliferation

Genetic studies

Many loci have been implicated in the condition [42]. Most recently, a number of recent breakthroughs have dramatically advanced our understanding of ASC from the standpoint of human genetics and neuropathology. These studies highlight the period of foetal development and the processes of chromatin structure, synaptic function, and neuron-glial signalling [18]. A key component of genetic architecture is the allelic spectrum influencing trait variability. Recent studies have demonstrated that the total heritability of risk-associated genes is in the range of 50–60 % with common variants explaining the bulk of it [40]. In a comparison of genome-wide linkage studies between autoimmune and inflammatory disorders in ASC, overlap of polymorphic markers were statistically significant [8]. For a comprehensive list of the genes identified, see http://www.grc.nia.nih.gov/branches/rrb/dna/atsmap.htm.

Where it is conceded that the chromosomal regions identified in these linkage studies and the specific variants of genes identified in genetic association studies are quite often not unique to any one disorder [8]. Specific immunological genetic assays have been tested in panelled assays to test both sensitivity and specificity in diagnosing autism. Using a signature of differentially co-expressed genes that were enriched in translation and immune/inflammation function, the authors were able to identify boys with autism with 83 % accuracy [85].

Extracellular mediators

Maternal-foetal transfer

The involvement of an inflammatory pathogenesis in ASC likely originates during the gestational period [59]. Autoantibodies are transferred from the mother to the child during pregnancy and are associated with a number of factors that affect both pregnancy and neonatal outcome [100]. In a cohort of mothers of children with ASC, autoantibodies have been detected against critical neuronal components of foetal brain tissue samples [109] as well as transfer of maternal neuro-specific proteins [23]. These studies identified a range of unknown protein targets ranging from 30 to 250 kilodaltons (kDa) in size. Consecutive independent studies have identified autoantibodies that bind to novel proteins of 37, 39, and 73 kDa in size [39, 104].

A number of models have been hypothesised to explain the transfer of anti-foetal brain autoantibodies [58]. In one study, immunoglobulin G (IgG) isolated from mothers with children with ASC was transferred into rhesus macaque monkeys during mid-gestation and resulted in distinct behavioural changes in the offspring. In particular, the monkeys spent significantly less time in contact with their peers and spent more time in a non-social state. This was attributed to the specific IgG from mothers of children with ASC infusion and not observed in monkeys receiving IgG from control donors or monkeys that were saline treated [7, 65]. These observations have been replicated in mice [15, 93]. Whether the transfer of these auto-antibodies during gestation plays a role in the pathogenesis in ASC remains uncertain; however, it is clear that there is a potential association. Brimberg et al. [13] describes mothers of an ASC child being found to be four times more likely to harbour anti-brain antibodies than other women of child-bearing age. Fundamentally, these processes may have a significant impact on neurodevelopment. Supporting this view is a recent study from Braunschweig et al. [11] who have identified that lactate dehydrogenases A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2), and Y-box-binding protein comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. This built on previous work which introduced the concept of studying the maternal plasma antibodies against both the maternal and fatal brain [12, 24, 87].

A number of animal studies have demonstrated that placenta to foetus transport can alter development. Specifically, Lin et al. [63] used P. gingivalis in mice to demonstrate that maternal immune system stimulation can lead to elevated levels of pro-inflammatory cytokines in both the placenta and amniotic fluid, whilst at the same time decreasing the major anti-inflammatory cytokines TGF-β, IL-4, and IL-10. Maternal inoculation with Poly(I:C), as well as lipopolysaccharide (LPS), also in mice, have resulted in the animal displaying behavioural characteristics in keeping with ASC, including pre-pulse inhibition deficits, working memory deficits, and social interaction deficits [80]. Blocking the action of these pro-inflammatory cytokines during maternal infection was observed to inhibit the development of such behaviour [52, 80]. Maternal LPS administration upregulates both tumour necrosis factor-alpha (TNF-α) and IL-1β mRNA expression in the foetuses of pregnant rats in a dose-dependent manner [38].

Cytokines and chemokines

Cytokines and chemokines are pleiotrophic proteins that coordinate the host response to infection as well as mediate normal, ongoing communication between cells of non-immune tissues, including the nervous system [27]. As a consequence of this dual role, cytokines induced in response to an adverse stimuli (i.e. maternal infection or prenatal hypoxia) can profoundly impact fetal neurodevelopment. Aberrant levels of proinflammatory cytokines, interleukin 6 (IL-6), TNF-α and monocyte chemotactic protein-1 (MCP-1), not only in brain specimens and cerebrospinal fluid (CSF; [90, 101]) but also in amniotic fluid [1], index an active inflammatory process both in children and adults with ASC. These molecules act to increase immune cell recruitment and proliferation. Immune pathways are activated by proinflammatory cytokines such as TNF-α and IL-6 that stimulate the nuclear translocation of various transcription factors, including NF-κB that subsequently results in the potentiation of the immune response [81]. This is tightly controlled in acute infection and lasts for a limited time. However, the presence of such molecules in the absence of an acute stimulus is an atypical response. An atypical inflammatory response has been observed in peripheral samples to show similar changes [56] as well as decreases in anti-inflammatory protein IL-10 [56]. In a larger multi-analyte profiling (MAP) analysis, Suzuki et al. [98] reported from a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17, and growth regulated oncogene-alpha (GRO-α) were significantly higher in individuals with ASC compared with the corresponding values of matched controls, after correction for multiple comparisons. Upregulation of inflammation-related molecules has also been found to be characteristic for adult males (but not females) with Asperger syndrome [95]. In mid-gestation maternal serum, elevated concentrations of IFN-γ, IL-4, and IL-5 were significantly associated with a 50 % increased risk of ASC, regardless of ASC onset type and the presence of intellectual disability [45].

The main issue surrounding the reporting of serum results is that they show considerable within- and between-group variability. As such, the subtle differences found may indicate the presence of separate subgroups of the condition [60]. For example, statistical clustering analysis on large-scale clinical data suggests the presence of subgroups with ASC characterised by co-occurrence of infectious disorder [31], which could be related to physiological atypicality related to inflammatory processes. Further analysis using appropriately powered studies will be required in order to gauge the potential explanatory power of this hypothesis.

Cell surface proteins

In contrast to cytokines and chemokines, major histocompatibility complex (MHC) family members have very short intracellular domains not thought to function in intracellular signalling cascades, but instead by interacting with a variety of receptors during cell-mediated immunity [92]. Together with TLRs, they form a key role in activity-dependent brain development and plasticity as well as regulating the immune response [84]. Specifically, it has been observed that (MHC) class I molecule H2-D(b) is essential for synapse elimination in the retinogeniculate system [62, 67].

Genetically, immune dysfunction in ASC has been suggested to included the MHC region, as this is an immunologic gene cluster whose gene products are class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The human leukocyte antigen (HLA) genes are among the strongest predictors of risk for autoimmune conditions. Some studies have observed that different HLA haplotypes are associated with neurodevelopmental conditions such as ASC [19, 55] and schizophrenia [94]. Stubbs et al. [97] initially demonstrated that mothers of children with ASC share HLA haplotypes with their children more often than in non-affected pairs. Recent evidence has suggested that impairments of innate immunity, originating with cell surface proteins, may play an important role in ASC. Enstrom et al. [33] demonstrated an improved responsiveness to signalling via select TLRs: TLR 2, TLR 4, and conversely a decreased production of cytokines following stimulation of TLR 9.

Intracellular signalling pathways

Another distinct pathway to be implicated in ASC is a well-known family of transcription factors, the nuclear factor kappa B (NF-κB), which is one of the key players in the regulation of inflammatory responses [77, 81]. This transcription factor is constitutively expressed in the cytoplasm and is inhibited by inhibitor κB (I κB), which binds NF-κB, masking its nuclear localization signal and retaining it in the cytoplasm [44]. NF-κB activity is attributed to Rel/NF-κB family proteins forming homodimers and heterodimers through the combination of the subunits p65 (or RelA), p50, p52, c-Rel, or RelB [81]. Cytokines, chemokines, and reactive oxygen species are among a number of key mediators that induce NF-κB by activating IκB kinases [77]. These phosphorylate IκBα, leading to its polyu biquitination and degradation [43], allow NF-κB to migrate to the nucleus, where it activates the transcription of various proinflammatory genes.

NF-κB has been found to be aberrantly expressed in the orbitofrontal cortex in postmortem studies of adults with ASC [107]. Expression was most abundant in microglia followed by astrocytes compared to neurons. However, samples from other frontal lobe or cerebellar samples have not shown similar increases [64] suggesting a localisation of aberrant expression. Peripherally, NF-κB was upregulated in TNF-α and LPS stimulated peripheral blood monocytes (PBMCs) [71]. The upregulation of expression was found to be similar in that Young et al. [107] reported a 2.9-fold increase in NF-κB expression centrally compared to a 2.2-fold increase reported peripherally [71]. The significance of this similarity is difficult to ascertain as there is significant heterogeneity of brain parenchyma in response to inflammatory stimuli [108]. The implication of the NF-κB signalling pathway in ASC further supports a potential role for neuroinflammation. Further work is needed to identify whether upregulation of NF-κB plays a role in initiating the signalling cascade or whether it is a result of aberrant stimulation.

Neuroanatomical changes

The ultrastructural morphology in ASC has been described as having atypical microglial and astroglial activation [101]. Prominent histological changes have been described in the cerebellum, characterised by a patchy loss of neurons in the Purkinje cell layer (PCL) and granular cell layer (GCL) [101] as well as a reduction in neuron number in the amygdalae and fusiform gyrus [89]. Glial activation has been widely observed throughout a number of independent studies. Vargas et al. [101] observed an increase in glial fibrillary acidic protein (GFAP) concentration in the white matter of the middle frontal gyrus (MFG) and anterior cingulate gyrus (ACG). An increased ratio of CD11c-positive, mature (highly active) microglia was observed in the orbitofrontal cortex and showed strong correlation with cell signalling molecules [107]. Microglial activation and increased microglial density was also observed in the dorsolateral prefrontal cortex in ASC [69]. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes [69]. They also described a significant increase in microglial somal volume in the white matter. Microglial cell density was increased in the grey matter with non-significant trends in somal volume [69]. A recent study by Paolicelli and Gross [78] suggests a central role for microglia in synaptic pruning, a process that has been suggested to be aberrant in the developing brain in ASC [22].

Magnetic resonance spectroscopy (MRS) has provided significant insight into the ultrastructural morphology in ASC. Myo-inositol (Ins) is a metabolic compound located mostly in astrocytes. High Ins levels are thought to indicate an increase in astrocyte populations and are particularly abundant in neuroinflammation [10]. Interestingly, increased Ins levels have been demonstrated to impact on performance IQ scores in individuals with ASC [37].

The resonance group attributed to the glutamine-glutamate-GABA complex (Glx) includes contributions from both glutamate and its precursor glutamine. Very little glutamate penetrates the blood–brain barrier, so local synthesis is essential. De novo synthesis is mediated mainly by astrocytes, and as such, in vivo levels can be altered in neuroinflammation [61]. Glutamate synthesised by astrocytes is converted to glutamine via the enzyme glutamine synthetase and exported to neurons via multiple transporters [26]. In neurons, glutamine is reconverted into glutamate using the mitochondrial enzyme phosphate-activated glutaminase and then packaged into synaptic vesicles for release [61]. Release of glutamate initiates signalling events in excitatory neurotransmission; transmission is terminated by the removal of glutamate from the extracellular space, predominantly via astrocytic glutamate transporters. This overall cycle of synthesis, release, and recovery of glutamate is referred to as the glutamate–glutamine cycle [50].

DeVito et al. [28] described widespread decrease in N-acetylaspartate (NAA) and Glx among people with ASC, with reductions observed in both the cerebral grey matter and the cerebellum. In a sample of adults with ASC, there was also a significant decrease in concentration of Glx, as well as choline, creatine (Cr) and NAA, in the basal ganglia [51]. A reduction in Glx would classically be attributed to a reduction in neuron density. Nevertheless, inflammatory molecules can also contribute to inhibiting the astrocytic glutamate reuptake [53] and by inducing changes in glutamate receptor subunit expression, thus leading to reduced intracellular levels of Glx [4].

Specificity of neuroinflammation

Neuroinflammation is emerging as a common finding in neurological and neuropsychiatric phenotypes. Most recently, it emerged as a finding in large genetic analyses of schizophrenia, bipolar disorder, and major depression [75]. This prompts the question of the specificity of inflammation as a contributing mechanism in the emergence of ASC. Furthermore, it promotes ongoing discussion on whether this is a causal or reactive process. What is certain is that, regardless of whether inflammation is specific to a condition or general to a majority of psychiatric conditions, if it is present, it should be treated and whether it forms part of a multisystme pathology, it should be treated and the response evaluated to observe whether there is a significant cognitive change. Clarifying the roles of various neuroinflammatory processes, causal (aetiological) or reactive, in neurodevelopmental conditions, also serves as a useful angle to delineate ubiquitous pathogenetic processes across all kinds of atypical neurodevelopment from specific mechanisms or reactive processes that mark one clinical diagnosis but not others.

Evidence against inflammation as a contributing mechanism in autism

There have been a few studies that failed to identify atypical inflammatory activity in ASC [64, 102]. Voineagu et al. [102] detail that the immune changes observed in their study of convergent molecular pathology have a less pronounced genetic component and thus are most likely either secondary phenomena or caused by environmental factors. Some have even gone as far to say that there is evidence that the immune response is not overactivated [64]. Whilst these studies are important, they have not been replicated to the extent of papers supporting a role for inflammation in the pathogenesis of ASC. It is also important to consider that the scale of the inflammatory response is so vast that it is possible to target inflammatory mediators which may not contribute to the condition. This is well presented in a recent meta-analysis looking at the cytokine response in autism [66]. Where 19 cytokines were assessed, only 7 were observed to have significantly different levels in ASC.

Conclusions

An emerging focus of research into the aetiology of ASC has suggested neuroinflammation as one candidate underlying biological model. With over 1000 candidate genes associated with it, ASC has a strong genetic component [70]. Similar to most medical conditions, however, there is also a significant environmental component in place, through gene-environmental interplay such as epigenetic mechanisms. The study of inflammation in ASC provides an excellent opportunity to dissect potential gene-environmental interplay. Here, we have highlighted some of the common indications of immunological dysregulation as potential contributing pathogenic processes for, at least certain subgroups of, individuals with ASC. Nevertheless, it is unclear whether the role of inflammation in ASC induces epigenetic change, via the activation of signalling cascades, or whether it is a direct result of genetic mutation and downstream effects. Whilst there is a growing body of work to support the role of inflammation in ASC, the greatest area of weakness in the field is that in general, the findings tend to be from individual studies and rarely are these replicated. Future work is needed to demonstrate what are essentially preliminary findings in large-scale studies. How much of a role, if any, neuroinflammation has on the emergence of ASC and contributing to its aetiological heterogeneity remains to be clarified.

Abbreviations

ASC: 

autism spectrum condition

NF-κB: 

nuclear factor kappa-light-chain enhancer of activated B cells

Declarations

Acknowledgements

SBC was supported by the MRC and the Autism Research Trust and M-CL by the William Binks Autism Neuroscience Fellowship, during the period of this work.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK
(2)
School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
(3)
Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Science, University of Reading, Reading, UK
(4)
Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada
(5)
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
(6)
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK
(7)
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
(8)
CLASS Clinic, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

References

  1. Abdallah MW, Larsen N, Grove J, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, et al. Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study. Cytokine. 2013;61(2):370–6. doi:10.1016/j.cyto.2012.11.015.PubMedView ArticleGoogle Scholar
  2. Anderson AA, Ushakov DS, Ferenczi MA, Mori R, Martin P, Saffell JL. Morphoregulation by acetylcholinesterase in fibroblasts and astrocytes. J Cell Physiol. 2008;215(1):82–100.PubMedView ArticleGoogle Scholar
  3. Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, et al. Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol. 2008;204(1-2):149–53.PubMedPubMed CentralView ArticleGoogle Scholar
  4. Balosso S, Ravizza T, Pierucci M, Calcagno E, Invernizzi R, Di Giovanni G, et al. Molecular and functional interactions between tumor necrosis factor-alpha receptors and the glutamatergic system in the mouse hippocampus: implications for seizure susceptibility. Neuroscience. 2009;161(1):293–300.PubMedView ArticleGoogle Scholar
  5. Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci. 2002;6(6):248–54.PubMedView ArticleGoogle Scholar
  6. Baron-Cohen S, Leslie AM, Frith U. Does the autistic child have a “theory of mind”? Cognition. 1985;21(1):37–46.PubMedView ArticleGoogle Scholar
  7. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. 2013;3:e278. doi:10.1038/tp.2013.47.PubMedPubMed CentralView ArticleGoogle Scholar
  8. Becker KG. Autism, asthma, inflammation, and the hygiene hypothesis. Med Hypotheses. 2007;69(4):731–40.PubMedPubMed CentralView ArticleGoogle Scholar
  9. Beart PM, O’Shea RD. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol. 2007;150(1):5–17.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Bernardi S, Anagnostou E, Shen J, Kolevzon A, Buxbaum JD, Hollander E, et al. In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism. Brain Res. 2011;1380:198–205.PubMedPubMed CentralView ArticleGoogle Scholar
  11. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry. 2013;3:e277.PubMedPubMed CentralView ArticleGoogle Scholar
  12. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 2008;29(2):226–31.PubMedPubMed CentralGoogle Scholar
  13. Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol Psychiatry. 2013;18(11):1171–7.PubMedView ArticleGoogle Scholar
  14. Buehler MR. A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. Med Hypotheses. 2011;76(6):863–70.PubMedView ArticleGoogle Scholar
  15. Camacho J, Jones K, Miller E, Ariza J, Noctor S, Van de Water J, et al. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behav Brain Res. 2014;266:46–51. doi:10.1016/j.bbr.2014.02.045.PubMedPubMed CentralView ArticleGoogle Scholar
  16. Castedo M, Perfettini JL, Roumier T, Kroemer G. Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ. 2002;9(12):1287–93.PubMedView ArticleGoogle Scholar
  17. Chawarska K, Shic F, Macari S, Campbell DJ, Brian J, Landa R, et al. 18-month predictors of later outcomes in younger siblings of children with autism spectrum disorder: a baby siblings research consortium study. J Am Acad Child Adolesc Psychiatry. 2014;53(12):1317–27.PubMedPubMed CentralView ArticleGoogle Scholar
  18. Chen JA, Peñagarikano O, Belgard TG, Swarup V, Geschwind DH. The emerging picture of autism spectrum disorder: genetics and pathology. Annu Rev Pathol. 2015;10:111–44.PubMedView ArticleGoogle Scholar
  19. Chien YL, Wu YY, Chen CH, Gau SS, Huang YS, Chien WH, et al. Association of HLA-DRB1 alleles and neuropsychological function in autism. Psychiatr Genet. 2012;22(1):46–9.PubMedView ArticleGoogle Scholar
  20. Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord. 2007;37(4):738–47.PubMedView ArticleGoogle Scholar
  21. Courchesne E, Campbell K, Solso S. Brain growth across the life span in autism: age-specific changes in anatomical pathology. Brain Res. 2011;1380:138–45.PubMedPubMed CentralView ArticleGoogle Scholar
  22. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306(18):2001–10.PubMedView ArticleGoogle Scholar
  23. Croen LA, Goines P, Braunschweig D, Yolken R, Yoshida CK, Grether JK, et al. Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study. Autism Res. 2008;1(2):130–7.PubMedPubMed CentralView ArticleGoogle Scholar
  24. Croen LA, Braunschweig D, Haapanen L, Yoshida CK, Fireman B, Grether JK, et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry. 2008;64(7):583–8.PubMedPubMed CentralView ArticleGoogle Scholar
  25. Cusco I, Medrano A, Gener B, Vilardell M, Gallastegui F, Villa O, et al. Autism-specific copy number variants further implicate the phosphatidylinositol signaling pathway and the glutamatergic synapse in the etiology of the disorder. Hum Mol Genet. 2009;18(10):1795–804.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Deitmer JW, Broer A, Broer S. Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem. 2003;87(1):127–35.PubMedView ArticleGoogle Scholar
  27. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78.PubMedView ArticleGoogle Scholar
  28. DeVito TJ, Drost DJ, Neufeld RW, Rajakumar N, Pavlosky W, Williamson P, et al. Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry. 2007;61(4):465–73.PubMedView ArticleGoogle Scholar
  29. DSM-IV® Sourcebook (1994) American Psychiatric Association. ISBN 978-0-89042-025-6.Google Scholar
  30. DSM-V® Sourcebook (2013) American Psychiatric Association. ISBN 978-0-89042-065-2Google Scholar
  31. Doshi-Velez F, Ge Y, Kohane I. Comorbidity clusters in autism spectrum disorders: an electronic health record time-series analysis. Pediatrics. 2014;133(1):e54–63. doi:10.1542/peds.2013-0819.PubMedPubMed CentralView ArticleGoogle Scholar
  32. Engstrom M, Karlsson R, Jonsson JI. Inactivation of the forkhead transcription factor FoxO3 is essential for PKB-mediated survival of hematopoietic progenitor cells by kit ligand. Exp Hematol. 2003;31(4):316–23.PubMedView ArticleGoogle Scholar
  33. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun. 2010;24(1):64–71.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31(6):529–35.PubMedView ArticleGoogle Scholar
  35. Frith U. A new look at language and communication in autism. Br J Disord Commun. 1989;24(2):123–50.PubMedView ArticleGoogle Scholar
  36. Fujii E, Mori K, Miyazaki M, Hashimoto T, Harada M, Kagami S. Function of the frontal lobe in autistic individuals: a proton magnetic resonance spectroscopic study. J Med Invest. 2010;57(1-2):35–44.PubMedView ArticleGoogle Scholar
  37. Gabis L, Wei H, Azizian A, DeVincent C, Tudorica A, Kesner-Baruch Y, et al. 1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders. J Child Neurol. 2008;23(7):766–74.PubMedView ArticleGoogle Scholar
  38. Gao YX, Cai FC. Experimental study on the therapeutic mechanism of high dose intravenous immunoglobulin in treatment of immune-mediated peripheral neuropathy. Zhonghua Er Ke Za Zhi. 2003;41(9):684–7.PubMedGoogle Scholar
  39. Garty BZ, Ludomirsky A, Danon YL, Peter JB, Douglas SD. Placental transfer of immunoglobulin G subclasses. Clin Diagn Lab Immunol. 1994;1(6):667–9.PubMedPubMed CentralGoogle Scholar
  40. Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al. Most genetic risk for autism resides with common variation. Nat Genet. 2014;46(8):881–5.PubMedPubMed CentralView ArticleGoogle Scholar
  41. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007;17(1):103–11.PubMedView ArticleGoogle Scholar
  42. Geschwind DH, State MW. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 2015;16.Google Scholar
  43. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81–96.PubMedView ArticleGoogle Scholar
  44. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.PubMedView ArticleGoogle Scholar
  45. Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, et al. Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol Autism. 2011;2:13-2392-2-13.View ArticleGoogle Scholar
  46. Happé F, Frith U. The weak coherence account: detail-focused cognitive style in autism spectrum disorders. J Autism Dev Disord. 2006;36(1):5–25. Review.PubMedView ArticleGoogle Scholar
  47. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.PubMedView ArticleGoogle Scholar
  48. Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A. Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genet A. 2007;143(6):589–93.View ArticleGoogle Scholar
  49. Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough? Genet Med. 2007;9(5):268–74.PubMedView ArticleGoogle Scholar
  50. Hertz L. The astrocyte-neuron lactate shuttle: a challenge of a challenge. J Cereb Blood Flow Metab. 2004;24(11):1241–8.PubMedView ArticleGoogle Scholar
  51. Horder J, Lavender T, Mendez MA, O’Gorman R, Daly E, Craig MC, et al. Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study. Transl Psychiatry. 2013;3:e279.PubMedPubMed CentralView ArticleGoogle Scholar
  52. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451–63.PubMedPubMed CentralView ArticleGoogle Scholar
  53. Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation. 2000;7(3):153–9.PubMedView ArticleGoogle Scholar
  54. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A. 2010;107(16):7455–60.PubMedPubMed CentralView ArticleGoogle Scholar
  55. Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA, et al. HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med. 2009;163(6):542–6.PubMedView ArticleGoogle Scholar
  56. Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology. 2002;46(2):76–84.PubMedView ArticleGoogle Scholar
  57. Kern KL. The possible role of the cerebellum in autism/PDD: disruption of a multisensory feedback loop. Med Hypotheses. 2002;59(3):255–60.PubMedView ArticleGoogle Scholar
  58. Klauck SM. Genetics of autism spectrum disorder. Eur J Hum Genet. 2006;14(6):714–20.PubMedView ArticleGoogle Scholar
  59. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643–60.PubMedView ArticleGoogle Scholar
  60. Lai MC, Lombardo MV, Chakrabarti B, Baron-Cohen S. Subgrouping the autism “spectrum”: reflections on DSM-5. PLoS Biol. 2013;11(4):e1001544.PubMedPubMed CentralView ArticleGoogle Scholar
  61. Lee A, Pow DV. Astrocytes: glutamate transport and alternate splicing of transporters. Int J Biochem Cell Biol. 2010;42(12):1901–6.PubMedView ArticleGoogle Scholar
  62. Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S, Feller MB, et al. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature. 2014;509(7499):195–200.PubMedPubMed CentralView ArticleGoogle Scholar
  63. Lin D, Smith MA, Champagne C, Elter J, Beck J, Offenbacher S. Porphyromonas gingivalis infection during pregnancy increases maternal tumor necrosis factor alpha, suppresses maternal interleukin-10, and enhances fetal growth restriction and resorption in mice. Infect Immun. 2003;71(9):5156–62.PubMedPubMed CentralView ArticleGoogle Scholar
  64. Malik M, Tauqeer Z, Sheikh AM, Wen G, Nagori A, Yang K, et al. NF-κB signaling in the brain of autistic subjects. Mediators Inflamm. 2011;2011:785265. doi:10.1155/2011/785265. Erratum in: Mediators Inflamm. 2013;2013:691975.PubMedPubMed CentralView ArticleGoogle Scholar
  65. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun. 2008;22(6):806–16.PubMedPubMed CentralView ArticleGoogle Scholar
  66. Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2015;20(4):440–6.PubMedView ArticleGoogle Scholar
  67. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry. 2014;75(4):262–8.PubMedPubMed CentralView ArticleGoogle Scholar
  68. Mondino A, Mueller DL. mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol. 2007;19(3):162–72.PubMedPubMed CentralView ArticleGoogle Scholar
  69. Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry. 2010;68(4):368–76.PubMedView ArticleGoogle Scholar
  70. Murdoch JD, State MW. Recent developments in the genetics of autism spectrum disorders. Curr Opin Genet Dev. 2013;23(3):310–5.PubMedView ArticleGoogle Scholar
  71. Naik US, Gangadharan C, Abbagani K, Nagalla B, Dasari N, Manna SK. A study of nuclear transcription factor-kappa B in childhood autism. PLoS ONE. 2011;6(5):e19488.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Neuhaus E, Beauchaine TP, Bernier R. Neurobiological correlates of social functioning in autism. Clin Psychol Rev. 2010;30(6):733–48.PubMedView ArticleGoogle Scholar
  73. Nordahl CW, Lange N, Li DD, Barnett LA, Lee A, Buonocore MH, et al. Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders. Proc Natl Acad Sci U S A. 2011;108(50):20195–200. doi:10.1073/pnas.1107560108.PubMedPubMed CentralView ArticleGoogle Scholar
  74. Nordahl CW, Scholz R, Yang X, Buonocore MH, Simon T, Rogers S, et al. Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study. Arch Gen Psychiatry. 2012;69(1):53–61.PubMedPubMed CentralView ArticleGoogle Scholar
  75. O’Dushlaine & The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015;18:199–209.View ArticleGoogle Scholar
  76. Ozonoff S, Rogers SJ, Farnham JM, Pennington BF. Can standard measures identify subclinical markers of autism? J Autism Dev Disord. 1993;23(3):429–41.PubMedView ArticleGoogle Scholar
  77. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6853–66.PubMedView ArticleGoogle Scholar
  78. Paolicelli RC, Gross CT. Microglia in development: linking brain wiring to brain environment. Neuron Glia Biol. 2011;7(1):77–83.PubMedView ArticleGoogle Scholar
  79. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17(6):485–95.PubMedView ArticleGoogle Scholar
  80. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology, and animal models. Behav Brain Res. 2008;12:121–8.Google Scholar
  81. Perkins ND. NF-kappaB: tumor promoter or suppressor? Trends Cell Biol. 2004;14(2):64–9.PubMedView ArticleGoogle Scholar
  82. Plaisted K, O’Riordan M, Baron-Cohen S. Enhanced visual search for a conjunctive target in autism: a research note. J Child Psychol Psychiatry. 1998;39:777–83.PubMedView ArticleGoogle Scholar
  83. Plaisted K, O’Riordan M, Baron-Cohen S. Enhanced discrimination of novel, highly similar stimuli by adults with autism during a perceptual learning task. J Child Psychol Psychiatry. 1998;39:765–75.PubMedView ArticleGoogle Scholar
  84. Prabowo AS, Iyer AM, Anink JJ, Spliet WG, Rijen PC, Aronica E. Differential expression of major histocompatibility complex class I in developmental glioneuronal lesions. J Neuroinflammation. 2013;10:12.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C, et al. Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry. 2015;72(4):386–94.PubMedView ArticleGoogle Scholar
  86. Sacco R, Militerni R, Frolli A, Bravaccio C, Gritti A, Elia M, et al. Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiatry. 2007;62(9):1038–47.PubMedView ArticleGoogle Scholar
  87. Sadiq FA, Slator L, Skuse D, Law J, Gillberg C, Minnis H. Social use of language in children with reactive attachment disorder and autism spectrum disorders. Eur Child Adolesc Psychiatry. 2012;21(5):267–76.PubMedView ArticleGoogle Scholar
  88. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008;105(22):7797–802.PubMedPubMed CentralView ArticleGoogle Scholar
  89. Schumann CM, Nordahl CW. Bridging the gap between MRI and postmortem research in autism. Brain Res. 2011;1380:175–86.PubMedPubMed CentralView ArticleGoogle Scholar
  90. Schwarz E, Guest PC, Rahmoune H, Wang L, Levin Y, Ingudomnukul E, et al. Sex-specific serum biomarker patterns in adults with Asperger’s syndrome. Mol Psychiatry. 2011;16(12):1213–20.PubMedView ArticleGoogle Scholar
  91. Shin JW, Nguyen KT, Pow DV, Knight T, Buljan V, Bennett MR, et al. Distribution of glutamate transporter GLAST in membranes of cultured astrocytes in the presence of glutamate transport substrates and ATP. Neurochem Res. 2009;34(10):1758–66.PubMedView ArticleGoogle Scholar
  92. Shatz CJ. MHC class I: an unexpected role in neuronal plasticity. Neuron. 2009;64(1):40–5.PubMedPubMed CentralView ArticleGoogle Scholar
  93. Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J Neuroimmunol. 2009;211(1-2):39–48.PubMedView ArticleGoogle Scholar
  94. Singh B, Bera NK, De S, Nayak C, Chaudhuri TK. Study of HLA class I gene in Indian schizophrenic patients of Siliguri, West Bengal. Psychiatry Res. 2011;189(2):215–9.PubMedView ArticleGoogle Scholar
  95. Steeb H, Ramsey JM, Guest PC, Stocki P, Cooper JD, Rahmoune H, et al. Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. Mol Autism. 2014;5(1):4. doi:10.1186/2040-2392-5-4.PubMedPubMed CentralView ArticleGoogle Scholar
  96. Stubbs EG, Budden SS, Jackson RH, Terdal LG, Ritvo ER. Effects of fenfluramine on eight outpatients with the syndrome of autism. Dev Med Child Neurol. 1986;28(2):229–35.PubMedView ArticleGoogle Scholar
  97. Stubbs EG, Ritvo ER, Mason-Brothers A. Autism and shared parental HLA antigens. J Am Acad Child Psychiatry. 1985;24(2):182–5.PubMedView ArticleGoogle Scholar
  98. Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S, et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE. 2011;6(5):e20470.PubMedPubMed CentralView ArticleGoogle Scholar
  99. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007;318:71–6.PubMedPubMed CentralView ArticleGoogle Scholar
  100. Tincani A, Rebaioli CB, Frassi M, Taglietti M, Gorla R, Cavazzana I, et al. Pregnancy and autoimmunity: maternal treatment and maternal disease influence on pregnancy outcome. Autoimmun Rev. 2005;4(7):423–8.PubMedView ArticleGoogle Scholar
  101. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.PubMedView ArticleGoogle Scholar
  102. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380–4.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Voineagu I, Eapen V. Converging pathways in autism spectrum disorders: interplay between synaptic dysfunction and immune responses. Front Hum Neurosci. 2013;7:738.PubMedPubMed CentralView ArticleGoogle Scholar
  104. Warren RP, Cole P, Odell JD, Pingree CB, Warren WL, White E, et al. Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiatry. 1990;29(6):873–7.PubMedView ArticleGoogle Scholar
  105. Williams PG, Hersh JH. Brief report: the association of neurofibromatosis type 1 and autism. J Autism Dev Disord. 1998;28(6):567–71.PubMedView ArticleGoogle Scholar
  106. Wiznitzer M. Autism and tuberous sclerosis. J Child Neurol. 2004;19(9):675–9.PubMedGoogle Scholar
  107. Young AM, Campbell E, Lynch S, Suckling J, Powis SJ. Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation. Front Psychiatry. 2011;2:27.PubMedPubMed CentralView ArticleGoogle Scholar
  108. Young AM, Campbell E, Lynch S, Dunn M, Powis SJ. TNF-α induction of murine brain inflammation via IKK/NF kappa B signalling: a potential model for autism. PLoS ONE. 2012;7(6):e39049.PubMedPubMed CentralView ArticleGoogle Scholar
  109. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, et al. Maternal antibrain antibodies in autism. Brain Behav Immun. 2007;21(3):351–7.PubMedView ArticleGoogle Scholar
  110. Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005;33(3):195–201.PubMedView ArticleGoogle Scholar

Copyright

© Young et al. 2016

Advertisement

Molecular Autism

ISSN: 2040-2392