Implications For Autism Research Articles

A review of gene–environment correlations and their implications for autism: A conceptual model.

A conceptual model is proposed that explains how gene-environment correlations and the multiplier effect function in the context of social development in individuals with autism. The review discusses the current state of autism genetic research, including its challenges, such as the genetic and phenotypic heterogeneity of the disorder, and its limitations, such as the lack of interdisciplinary work between geneticists and social scientists. We discuss literature on gene-environment correlations in the context of social development and draw implications for individuals with autism. The review expands upon genes, behaviors, types of environmental exposure, and exogenous variables relevant to social development in individuals on the autism spectrum, and explains these factors in the context of the conceptual model to provide a more in-depth understanding of how the effects of certain genetic variants can be multiplied by the environment to cause largely phenotypic individual differences. Using the knowledge gathered from gene-environment correlations and the multiplier effect, we outline novel intervention directions and implications.

Social cognition and the superior temporal sulcus: Implications in autism

The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. These abnormalities are characterized by decreased grey matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomofunctional anomalies occurring early across brain development could constitute the first step in the cascade of neural dysfunctions underlying autism. It is known that STS is highly implicated on social perception processing, from perception of biological movements, such as body movements or eye gaze, to more complex social cognition processes. Among the impairments that can be described in social perception processing, eye gaze perception is particularly relevant in autism. Gaze abnormalities can now be objectively measured using eye-tracking methodology. In the present work, we will review recent data on STS contributions to normal social cognition and its implication in autism, with particular focus on eye gaze perception.

Developmental neuroscience of time and number: implications for autism and other neurodevelopmental disabilities.

Estimations of time and number share many similarities in both non-humans and man. The primary focus of this review is on the development of time and number sense across infancy and childhood, and neuropsychological findings as they relate to time and number discrimination in infants and adults. Discussion of these findings is couched within a mode-control model of timing and counting which assumes time and number share a common magnitude representation system. A basic sense of time and number likely serves as the foundation for advanced numerical and temporal competence, and aspects of higher cognition—this will be discussed as it relates to typical childhood, and certain developmental disorders, including autism spectrum disorder. Directions for future research in the developmental neuroscience of time and number (NEUTIN) will also be highlighted.

Aberrant T‐lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein‐α: implications for autism

Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

BackgroundArginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of AVPR1A in variable gene expression and social behaviour.MethodsWe examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity.ResultsThe short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.ConclusionsThese aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

Longitudinal effects of adaptability on behavior problems and maternal depression in families of adolescents with autism.

Research on families of individuals with autism has tended to focus on child-driven effects utilizing models of stress and coping. The current study used a family systems perspective to examine whether family level adaptability promoted beneficial outcomes for mothers and their adolescents with autism over time. Participants were 149 families of children diagnosed with autism who were between the ages of 10 and 22 years during the 3-year period examined. Mothers reported on family adaptability, the mother-child relationship, their own depressive symptoms, and the behavior problems of their children at Wave 1, and these factors were used to predict maternal depression and child behavior problems 3 years later. Family level adaptability predicted change in both maternal depression and child behavior problems over the study period, above and beyond the contribution of the dyadic mother-child relationship. These associations did not appear to depend upon the intellectual disability status of the individual with autism. Implications for autism, parent mental health, family systems theory, and intervention with this population are discussed.

Potential teratogenic effects of ultrasound on corticogenesis: Implications for autism

The phenotypic expression of autism, according to the Triple Hit Hypothesis, is determined by three factors: a developmental time window of vulnerability, genetic susceptibility, and environmental stressors. In utero exposure to thalidomide, valproic acid, and maternal infections are examples of some of the teratogenic agents which increase the risk of developing autism and define a time window of vulnerability. An additional stressor to genetically susceptible individuals during this time window of vulnerability may be prenatal ultrasound. Ultrasound enhances the genesis and differentiation of progenitor cells by activating the nitric oxide (NO) pathway and related neurotrophins. The effects of this pathway activation, however, are determined by the stage of development of the target cells, local concentrations of NO, and the position of nuclei (basal versus apical), causing consequent proliferation at some stages while driving differentiation and migration at others. Ill-timed activation or overactivation of this pathway by ultrasound may extend proliferation, increasing total cell number, and/or may trigger precipitous migration, causing maldistribution of neurons amongst cortical lamina, ganglia, white matter, and germinal zones. The rising rates of autism coincident with the increased use of ultrasound in obstetrics and its teratogenic/toxic effects on the CNS demand further research regarding a putative correlation.

Using “Bubbles” to Map Responses to Facial Features: Implications for Autism

Using “Bubbles” to Map Responses to Facial Features: Implications for Autism

Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy

Clinically, perturbations in the semaphorin signaling system have been associated with autism and epilepsy. The semaphorins have been implicated in guidance, migration, differentiation, and synaptic plasticity of neurons. The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. NPN2 signaling may intimately direct the apposition of presynaptic and postsynaptic locations, facilitating the development and maturity of hippocampal synaptic function. To further understand the role of NPN2 signaling in central nevous system (CNS) plasticity, structural and functional alterations were assessed in NPN2 deficient mice. In NPN2 deficient mice, we measured seizure susceptibility after kainic acid or pentylenetetrazol, neuronal excitability and synaptic throughput in slice preparations, principal and interneuron cell counts with immunocytochemical protocols, synaptosomal protein levels with immunoblots, and dendritic morphology with Golgi-staining. NPN2 deficient mice had shorter seizure latencies, increased vulnerability to seizure-related death, were more likely to develop spontaneous recurrent seizure activity after chemical challenge, and had an increased slope on input/output curves. Principal cell counts were unchanged, but GABA, parvalbumin, and neuropeptide Y interneuron cell counts were significantly reduced. Synaptosomal NPN2 protein levels and total number of GABAergic synapses were decreased in a gene dose-dependent fashion. CA1 pyramidal cells showed reduced dendritic length and complexity, as well as an increased number of dendritic spines. These data suggest the novel hypothesis that the Sema 3F signaling system's role in appropriate placement of subsets of hippocampal interneurons has critical downstream consequences for hippocampal function, resulting in a more seizure susceptible phenotype.

The physics of identifying with others: Implications for autism

The relationship between thought and motion in child development and what it might reveal about autism was the focus of a conference on 5-6 September. Richenda Power reports

Regulation of cerebral cortical size and neuron number by fibroblast growth factors: implications for autism.

Increased brain size is common in children with autism spectrum disorders. Here we propose that an increased number of cortical excitatory neurons may underlie the increased brain volume, minicolumn pathology and excessive network excitability, leading to sensory hyper-reactivity and seizures, which are often found in autism. We suggest that Fibroblast Growth Factors (FGF), a family of genes that regulate cortical size and connectivity, may be responsible for these developmental alterations. Studies in animal models suggest that mutations in FGF genes lead to altered cortical volume, excitatory cortical neuron number, minicolumn pathology, hyperactivity and social deficits. Thus, many risk factors may converge upon FGF-regulated pathogenetic pathways, which alter excitatory/inhibitory balance and cortical modular architecture, and predispose to autism spectrum disorders.

Approches substitutive et diététique du trouble autistique de l’enfant : intérêts ou limites ?

Resume L’application de complementations ou de regimes alimentaires specifiques sont pronees par certains auteurs dans le traitement du trouble autistique de l’enfant et cette approche suscite interet chez les parents et controverse chez les professionnels. Or, a ce jour, la majorite des etudes publiees sur ce theme dans le trouble autistique ne peuvent encourager les cliniciens a recommander les regimes aux parents du fait d’un manque de lisibilite de la balance benefice–risque. Les etudes souvent isolees et non repliquees par d’autres equipes souffrent d’une methodologie dont la rigueur s’avere insatisfaisante ou trop variable et seule la supplementation en vitamine B6 semblerait avoir repondu a des criteres d’evaluation, d’efficacite et de tolerance satisfaisants. Cette supplementation reste toutefois encore largement discutee. Mais l’approche dietetique n’est pas a negliger pour autant, car ces etudes temoignent du deficit nutritionnel des enfants autistes et de la confrontation des parents a leurs comportements alimentaires particuliers dont on ne peut ignorer le retentissement somatique, comportemental ou encore familial.

Cerebral O2 consumption in young Eker rats, effects of GABA blockade: implications for autism

Since there is a strong correlation between tuberous sclerosis and autism, we used a tuberous sclerosis model (Eker rat) to test the hypothesis that the increased regional cerebral O2 consumption in the Eker rat might be associated with autism. We also examined whether this increased cerebral O2 consumption was related to changes in the activity of the gamma-aminobutyric acid (GABA) inhibitory system. Young (4 weeks) male control Long Evans (n=14) and Eker (n=14) rats (70–100g) were divided into control and bicuculline (1mg/kg/min for 2min then 0.1mg/kg/min for 13min, GABAA receptor antagonist) treated animals. Cerebral regional blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. We found significantly increased basal O2 consumption in the cortex (6.3±0.7ml O2/min/100g Eker vs. 5.1±0.2ml O2/min/100g control), hippocampus and cerebellum, but not the pons. Regional cerebral blood flow was also elevated in the cortex and hippocampus in Eker rats at baseline, but cerebral O2 extractions were similar. Bicuculline significantly increased O2 consumption in the cortex (6.5±0.3) and all other regions of the control rats, but had no effect on cortex (5.9±1.5) or other regions of the Eker rats. Cerebral blood flow followed a similar pattern. In conclusion, Eker rats had significantly elevated cerebral O2 consumption and blood flow, but this was not affected by GABA receptor blockade. This suggested a reduced activity of the GABAA receptor in the brains of Eker rats. This may have important implications in the treatment of autism.

Increased cerebral oxygen consumption in Eker rats and effects of N‐methyl‐D‐aspartate blockade: Implications for autism

Because there is a strong correlation between tuberous sclerosis and autism, we used a tuberous sclerosis model (Eker rat) to test the hypothesis that these animals would have an altered regional cerebral O2 consumption that might be associated with autism. We also examined whether the altered cerebral O2 consumption was related to changes in the importance of N-methyl-D-aspartate (NMDA) receptors. Young (4 weeks) male control Long Evans (N = 14) and Eker (N = 14) rats (70-100 g) were divided into control and CGS-19755 (10 mg/kg, competitive NMDA antagonist)-treated animals. Cerebral regional blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. NMDA receptor protein levels were determined by Western immunoblotting. We found significantly increased basal O2 consumption in the cortex (6.2 +/- 0.6 ml O2/min/100 g Eker vs. 4.7 +/- 0.4 Long Evans), hippocampus, cerebellum, and pons. Regional cerebral blood flow was also elevated in Eker rats at baseline, but cerebral O2 extraction was similar. CGS-19755 significantly lowered O2 consumption in the cortex (2.8 +/- 0.3), hippocampus, and pons of the Long Evans rats but had no effect on cortex (5.8 +/- 0.8) or other regions of the Eker rats. Cerebral blood flow followed a similar pattern. NMDA receptor protein levels (NR1 subunit) were similar between groups. In conclusion, Eker rats had significantly elevated cerebral O2 consumption and blood flow, but this was not related to NMDA receptor activation. In fact, the importance of NMDA receptors in the control of basal cerebral O2 consumption was reduced. This might have important implications in the treatment of autism.

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Autism is a neurodevelopmental disorder presenting before 3 years of age with deficits in communication and social skills and repetitive behaviors. In addition to genetic influences, recent studies suggest that prenatal drug or chemical exposures are risk factors for autism. Terbutaline, a beta2-adrenoceptor agonist used to arrest preterm labor, has been associated with increased concordance for autism in dizygotic twins. We studied the effects of terbutaline on microglial activation in different brain regions and behavioral outcomes in developing rats. Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30. Immunohistochemical studies showed that administration of terbutaline on PN 2 to 5 produced a robust increase in microglial activation on PN 30 in the cerebral cortex, as well as in cerebellar and cerebrocortical white matter. None of these effects occurred in animals given terbutaline on PN 11 to 14. In behavioral tests, animals treated with terbutaline on PN 2 to 5 showed consistent patterns of hyper-reactivity to novelty and aversive stimuli when assessed in a novel open field, as well as in the acoustic startle response test. Our findings indicate that beta2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. This study provides a useful animal model for understanding the neuropathological processes underlying autism spectrum disorders.

Oxytocin, vasopressin and pair bonding: implications for autism.

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or 'microsatellite', in the 5' regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.

Understanding orbitofrontal contributions to theory-of-mind reasoning: Implications for autism

Autism is a lifelong developmental disorder that is associated with severe difficulties with “theory-of-mind”—the understanding that others’ behaviors are motivated by internal mental states. Here, we raise the possibility that research examining the neural bases of theory-of-mind reasoning has the potential to inform researchers about the elusive functional neural impairments associated with autism. Evidence from our lab and others’ suggests that theory-of-mind reasoning may be fractionated into at least two functionally and anatomically distinct neural circuits. Specifically, the ability to decode others’ mental states from observable cues (such as facial expressions) may rely on contributions from the orbitofrontal/medial temporal circuit within the right hemisphere. In contrast, the ability to reason about others’ mental states may rely left medial frontal regions. We conclude by reviewing evidence suggesting that the developmental roots of autism might lie in abnormal functioning of the orbitofrontal/medial temporal circuit which may, in turn, underlie the abnormal development of social-cognitive skills among individuals with autism.

Abnormal serotonergic development in a mouse model for the Smith–Lemli–Opitz syndrome: implications for autism

The Smith–Lemli–Opitz syndrome (SLOS) is a malformation/mental retardation syndrome resulting from an inborn error in 3β-hydroxysteroid Δ7-reductase (DHCR7), the terminal enzyme required for cholesterol biosynthesis. Using a targeting strategy designed to virtually eliminate Dhcr7 activity, we have created a SLOS mouse model that exhibits commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons. The latter is of particular interest with respect to current evidence that serotonin plays a significant role in autism spectrum disorders and the recent clinical observation that 50% of SLOS patients present with autistic behavior. Immunohistochemical analyses have revealed a 306% increase in the area of 5-HT immunoreactivity (5-HT IR) in the hindbrains of mutant (Dhcr7−/−) mice as compared to age-matched wild type animals. Amount of 5-HT IR was measured as total area of IR per histological section. Additionally, a regional increase as high as 15-fold was observed for the most lateral sagittal hindbrain sections. In Dhcr7−/− mice, an expansion of 5-HT IR into the ventricular zone and floor plate region was observed. In addition, the rostral and caudal raphe groups exhibited a radial expansion in Dhcr7−/− mice, with 5-HT IR cells present in locations not seen in wild type mice. This increase in 5-HT IR appears to represent an increase in total number of 5-HT neurons and fibers. These observations may help explain the behavioral phenotype seen in SLOS, and provide clues for future therapeutic interventions that utilize pharmacological modulation of the serotonergic system.

Editorial

The Annual Research Review is intended to provide the readership with updates in selected areas of current research. In this, the 13th Annual Research Review, I have again been pleased to work with an outstanding group of contributors to whom I extend my thanks. The comments of an outstanding set of referees have served to enrich both the papers and the authors and I extend our thanks to them as well. The charge to authors is to provide selective coverage of their topic area. By encouraging these selective reviews our hope is to provide a more interesting and readable set of papers for issues as the authors identify those findings which they feel have been of greatest importance for research over the past decade. In the first paper in this issue Caspi and Shiner have focused on personality differences in children and adolescents. This excellent review brings together a body of current and emerging work. In the next paper Grossman and colleagues discuss the effects of experience on brain development and its possible contributions to psychopathology. This review builds on the growing body of work on the effects of experience on the brain and its potential for providing new perspectives on understanding developmental and behavioral disorders. In their article Bachevalier and Machado discuss the uses and limitations of nonhuman primate models of psychopathology; this work may have particular implications for autism and similar disorders as we understand more about the role of specific brain mechanisms in mental disorders. In his paper Willoughby discuses the developmental course of symptoms of attention deficit hyperactivity disorder during the transition from childhood to adolescence and highlights areas important for future research. McMahon and colleagues have undertaken a review of the role of specificity of stress and psychopathology in children and adolescents; this review has particular importance as we attempt to understand how specific the role of stress is in producing specific symptomatology. Finally Woods and colleagues discuss potential parental contributions to children's experience of anxiety. For the 14th edition of the Annual Research Review we anticipate coverage of the following topics: autism and related disorders, assessment in infancy and early childhood, peer relations, outcome of low birthweight infants, learning disabilities, and cross-cultural perspectives on psychopathological disorders. Fred R. VolkmarAssociate Editor

Neurohumoral brain dynamics of social group formation. Implications for autism.

Brains are dynamic systems in which learning tends towards isolation by increasing specialization of cognitive skills. Induction of social skills for cooperative behavior requires "unlearning" in social contexts. A hypothesis is proposed by which oxytocin and related neuropeptides play a key role in meltdown of prior learning in preparation for new learning. This has implications for clinical management of disorders of the socialization processes in children.