Rodent Model Of Autism Research Articles

A multifaceted approach for analyzing complex phenotypic data in rodent models of autism

Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the “core” phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.

Regional and sex-dependent alterations in Purkinje cell density in the valproate mouse model of autism.

Neuropathological and neuroimaging studies indicate a decrease in Purkinje cell (PC) density in the cerebellum of autistic patients and rodent models of autism. Autism is far more prevalent in males than females, and sex-specific properties of PCs have been reported recently. We investigated the differential sensitivity of PCs in the valproate acid (VPA) mouse model of autism by estimating the linear density of PCs immununolabelled with calbindin in the cerebellum of males and females. Whereas prenatal VPA treatment surprisingly increased PC linear density in both sexes 13 days after birth (P13), it significantly reduced the linear density of PCs in the cerebellum of 40-day-old (P40) males, but not females. In males, PC loss was more pronounced in the posterior part of the cerebellum and was significant in the VIth, VIIth, IXth and paramedian lobules. In females, PC loss was restricted to the paramedian lobule. These results suggest that this sex-specific sensitivity of PCs to VPA may contribute towards the motor disturbances and behavioural abnormalities observed in autism.

Maternal and offspring methylenetetrahydrofolate-reductase genotypes interact in a mouse model to induce autism spectrum disorder-like behavior.

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co-occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate-reductase (MTHFR) 677C>T polymorphism, which impairs one-carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic-like behaviors. Maternal Mthfr-deficiency was associated with developmental delays in morphogenic features and sensory-motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex-dependent differences. Mthfr-deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in-utero and autonomous factors involved in autism.

A Multifaceted Approach for Analyzing Complex Phenotypic Data in Rodent Models of Autism

AutDB features a modular framework that aims at collating multifactorial risk factors associated with autism spectrum disorder (ASD). The animal model (AM) module of AutDB was first developed for mouse models of genes and CNVs associated with ASD (Kumar et al., 2011). Subsequently, environmentally induced rodent models were introduced to capture the full spectrum of risk-factors associated with ASD, along with idiopathic models represented by inbred strains. Using the data systematically annotated in AutDB, we depict the intricate trends in the research findings based on rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from 911 genetic, 269 induced and 17 inbred rodent models of ASD extracted from 787 publications. As expected, many of these include animal model equivalents of the 'core' phenotypes associated with ASD, as well as several comorbid features of ASD including anxiety, seizures and motor-control deficits. Uniquely, AutDB curates rescue models where various treatment strategies were used in rodent ASD models to alleviate ASD-relevant phenotypes. We further examine ASD models based on 52 genes and 2 CNV loci to identify 24 pharmaceutical agents that were used in 2 or more paradigms for testing their efficacy. As a case study, we analyze various Shank3 mouse models providing a high-resolution view of the in vivo role of this highconfidence ASD gene. Together, this resource provides a snapshot of genetic and induced models of ASD within a shared annotation platform to examine the complex meshing of diverse ASD-associated risk-factors. Funding Statement: This research was funded by the Simons Foundation. Declaration of Interests: Authors declare no competing interests.

Comparative study on the independent and combined effects of omega-3 and vitamin B12 on phospholipids and phospholipase A2 as phospholipid hydrolyzing enzymes in PPA-treated rats as a model for autistic traits

BackgroundAbnormal phospholipid metabolism is a major component of many neurodevelopmental disorders including autism. Oral administration of propionic acid (PPA) can produce behavioral abnormalities and biochemical features in rodents similar to those observed in autism and can thus be used as a model to understand impaired brain fatty acid metabolism in autism.MethodsThe present study was designed to understand alterations in phospholipid metabolism in the brain of a rodent model of autism and to explore omega-3 and vitamin B12 as remedies. Five groups of rats were selected: Group 1 was the control. Group 2 was the rodent model of autism treated with a neurotoxic dose of PPA. Group 3 was given vitamin B12 cobalamin (16.7 mg/kg/day) for 30 days after PPA treatment. Group 4 was given pharmaceutical grade Omega-3 (200 mg cholesterol free-DHA/kg body weight/day), a product of Madre lab, Germany, for 30 days after PPA treatment for 3 days. Group 5 was given a combined dose of ω-3 + Vitamin B12 for the same duration post-PPA treatment. Phospholipid levels and Phospholipase A2 were measured in the brain homogenates of all the groups. ELISA and western blotting were used to detect the cPLA2 protein level.ResultsA significant decrease in phospholipid levels and a significant increase in cPLA2 were found in brain tissue of PPA-treated rats; however, both ω-3 and vitamin B12 were efficient in ameliorating the neurotoxic effect of PPA.ConclusionBoth ω-3 and vitamin B12 may play a role in ameliorating impaired phospholipid metabolism in autism; however, proper clinical trials are needed.

Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism.

Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system. Specifically, people with autism have a reduction in parvalbumin (PV)-containing interneurons in the PFC, leading to the suggestion that restoring interneuron function in this region may be a novel therapeutic approach for ASD. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of PV-positive interneurons, which were transplanted into the medial prefrontal cortex (mPFC) of the Poly I:C rodent model of autism. PV interneuron transplants were able to decrease pyramidal cell firing in the mPFC and alleviated deficits in social interaction and cognitive flexibility. Our results suggest that restoring PV interneuron function in the mPFC may be a novel and effective treatment strategy to reduce the core symptoms of autism.

Rodent see, rodent fear.

To learn from others' experience, one must link environmental conditions with social cues. A specific amygdala circuit underlies social learning of fear, and targeted activation normalizes behavior in a rodent model of autism.

Potency of pre–post treatment of coenzyme Q10 and melatonin supplement in ameliorating the impaired fatty acid profile in rodent model of autism

BackgroundAbnormalities in fatty acid metabolism and membrane fatty acid composition play a part in a wide range of neurodevelopmental and psychiatric disorders. Altered fatty acid homeostasis as a result of insufficient dietary supplementation, genetic defects, the function of enzymes involved in their metabolism, or mitochondrial dysfunction contributes to the development of autism.ObjectiveThis study evaluates the association of altered brain lipid composition and neurotoxicity related to autism spectrum disorders in propionic acid (PA)–treated rats.DesignForty-eight young male western albino rats were used in this study. They were grouped into six equal groups with eight rats in each. The first group received only phosphate buffered saline (control group). The second group received a neurotoxic dose of buffered PA (250 mg/kg body weight/day for 3 consecutive days). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for 1 week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for 1 week prior to PA (protected groups). Methyl esters of fatty acid were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography.ResultsThe obtained data proved that fatty acids are altered in brain tissue of PA-treated rats. All saturated fatty acids were increased while all unsaturated fatty acids were significantly decreased in the PA-treated group and relatively ameliorated in the pre–post melatonin and coenzyme Q groups.ConclusionsMelatonin and coenzyme Q were effective in restoring normal level of most of the impaired fatty acids in PA-intoxicated rats which could help suggest both as supplements to ameliorate the autistic features induced in rat pups.

An urgent need for experimental animal model of autism in drug development.

Construct, face and predictive validities are necessary for any disease model. Although rodent models are used to investigate the neurobiology of autism, however, till date there is no such ideal animal model which can fulfill all the above said validities. Available drug therapy to treat autism is very limited and less effective. In this review, we summarize the work done with rodent models of autism and highlight different validities. We found that, very few studies have studied all the validities in a single study and none of the study fulfilled all the validities. We also reviewed the drugs used in the treatment of autism. Here we propose the limitations of available animal models. We also propose the urgent need of additional models to fulfill all the validities and to understand autism in a better way.

Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid

Autism is a severe neurodevelopmental disorder with a population prevalence of 1 in 68, and dramatically increasing. While no single pharmacologic intervention has successfully targeted the core symptoms of autism, emerging evidence suggests that postnatal environmental manipulations may offer greater therapeutic efficacy. Massage therapy, or tactile stimulation (TS), early in life has repeatedly been shown to be an effective, low-cost, therapeutic approach in ameliorating the cognitive, social, and emotional symptoms of autism. While early TS treatment attenuates many of the behavioral aberrations among children with autism, the neuroanatomical correlates driving such changes are unknown. The present study assessed the therapeutic effects of early TS treatment on behavior and neuroanatomy using the valproic acid (VPA) rodent model of autism. Rats were prenatally exposed to VPA on gestational day 12.5 and received TS shortly following birth. Whereas TS reversed almost all the VPA-induced alterations in neuroanatomy, it failed to do so behaviorally. The TS VPA animals, when compared to VPA animals, did not exhibit altered or improved behavior in the delayed non-match-to-sample T-maze, Whishaw tray reaching, activity box, or elevated plus maze tasks. Anatomically, however, there were significant increases in dendritic branching and spine density in the medial prefrontal cortex, orbital frontal cortex, and amygdala in VPA animals following early TS treatment, suggesting a complete reversal or remediation of the VPA-induced effects in these regions. The results suggest that postnatal TS, during a critical period in development, acts as a powerful reorganization tool that can ameliorate the neuroanatomical consequences of prenatal VPA exposure.

Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of γ-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth.

Relative abundance of short chain and polyunsaturated fatty acids in propionic acid-induced autistic features in rat pups as potential markers in autism.

BackgroundFatty acids are essential dietary nutrients, and one of their important roles is providing polyunsaturated fatty acids (PUFAs) for the growth and function of nervous tissue. Short chain fatty acids (SCFAs) are a group of compounds derived from the host microbiome that were recently linked to effects on the gut, the brain, and behavior. They are therefore linked to neurodevelopmental disorders such as autism. Reduced levels of PUFAs are associated with impairments in cognitive and behavioral performance, which are particularly important during brain development. Recent studies suggest that omega -3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are involved in neurogenesis, neurotransmission, and protection from oxidative stress. Omega-3 PUFAs mediate some of these effects by antagonizing Omega-6 PUFA (arachidonic acid, AA)-induced proinflammatory prostaglandin E2; (PGE2) formation.MethodsIn this work, the absolute and relative concentrations of propionic (PPA), butyric and acetic acids, as well as PUFAs and their precursors (α-Linolenic and linoleic), were measured in the brain tissue of PPA-neurointoxicated rat pups (receiving 250 mg PPA/Kg body weight for 3 consecutive days) as a rodent model with persistent autistic features compared with healthy controls.ResultsThe data revealed remarkably lower levels of omega6/omega3, α-Linolenic/Linoleic, α-Linolenic/EPA, α-Linolenic/DHA, EPA/DHA, and AA/Linoleic acid ratios in PPA-intoxicated rats. The role of these impaired ratios is discussed in relation to the activity of desaturases and elongases, which are the two enzymatic groups involved in the synthesis of PUFAs from their precursors. The relationship between the abnormal relative concentrations of the studied fatty acids and oxidative stress, neurotransmission, and neuroinflammation is also discussed in detail.ConclusionsThis study demonstrates that fatty acid ratios are useful for understanding the mechanism of PPA neurotoxicity in a rodent model of autism. Therefore, it is possible to use these ratios for predictions in patients with this disorder.

Auditory-cued sensorimotor task reveals disengagement deficits in rats exposed to the autism-associated teratogen valproic acid

Autism Spectrum Disorder (ASD) is often found to co-exist with non-core behavioral manifestations that include difficulties in disengagement of attention to sensory cues. Here we examined whether this behavioral abnormality can be induced in rats prenatally exposed to valproic acid (VPA), a well-established teratogen associated with ASD animal models. We tested rats using an auditory-cued sensorimotor task (ACST) based on the premise that ACST will be more sensitive to developmental changes in temporal association cortex (TeA) of the posterior attention system. We show that VPA rats learned the ACST markedly faster than control animals, but they exhibited a profound preoccupation with cues associated with the expectancy at the reward location such that disengagement was disrupted. Control rats on the other hand were able to disengage and utilize auditory cues for re-engagement. However, both control and VPA-treated rats performed similarly when tested on novel object recognition (NOR) and novel context mismatch (NOCM) behavioral tasks that are known to be sensitive to normal perirhinal and prefrontal network functioning respectively. Consistent with disrupted posterior rather than frontal networks, we also report that VPA can selectively act on deep-layer TeA cortical neurons by showing that VPA increased dendritic density in isolated deep-layer TeA but not frontal neurons. These results describe a useful approach to examine the role of cue-dependent control of attention systems in rodent models of autism and suggest that disengagement impairments may arise from an inability to modify behavior through the appropriate use of sensory cue associations.

Selected biomarkers as predictive tools in testing efficacy of melatonin and coenzyme Q on propionic acid - induced neurotoxicity in rodent model of autism.

BackgroundExposures to environmental toxins are now thought to contribute to the development of autism spectrum disorder. Propionic acid (PA) found as a metabolic product of gut bacteria has been reported to mimic/mediate the neurotoxic effects of autism. Results from animal studies may guide investigations on human populations toward identifying environmental contaminants that produce or drugs that protect from neurotoxicity. Forty-eight young male Western Albino rats were used in the present study. They were grouped into six equal groups 8 rats each. The first group received a neurotoxic dose of buffered PA (250 mg/Kg body weight/day for 3 consecutive days). The second group received only phosphate buffered saline (control group). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for one week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for one week prior to PA (protected groups). Heat shock protein70 (Hsp70), Gamma amino-butyric acid (GABA), serotonin, dopamine, oxytocin and interferon γ-inducible protein 16 together with Comet DNA assay were measured in brain tissues of the six studied groups.ResultsThe obtained data showed that PA caused multiple signs of brain toxicity revealed in depletion of GABA, serotonin, and dopamine, are which important neurotransmitters that reflect brain function, interferon γ-inducible protein 16 and oxytocin. A high significant increase in tail length, tail DNA% damage and tail moment was reported indicating the genotoxic effect of PA. Administration of melatonin or coenzyme Q showed both protective and therapeutic effects on PA–treated rats demonstrated in a remarkable amelioration of most of the measured parameters.ConclusionIn conclusion, melatonin and coenzyme Q have potential protective and restorative effects against PA-induced brain injury, confirmed by improvement in biochemical markers and DNA double strand breaks.

The Switch That Doesn't

Maternal administration of bumetanide before delivery reduces the autistic phenotype in rodent models of autism.

A CHEMICAL–GENETICS APPROACH TO STUDY THE MOLECULAR PATHOLOGY OF CENTRAL SEROTONIN ABNORMALITIES IN FETAL VALPROATE SYNDROME

Valproate (VPA) is a commonly used drug worldwide despite increased awareness of its adverse effects, especially when used during pregnancy. Fetal valproate syndrome, characterised by birth defects, learning difficulties, and...

Phosphorylation of FMRP and alterations of FMRP complex underlie enhanced mLTD in adult rats triggered by early life seizures

Outside of Fragile X syndrome (FXS), the role of Fragile-X Mental Retardation Protein (FMRP) in mediating neuropsychological abnormalities is not clear. FMRP, p70-S6 kinase (S6K) and protein phosphatase 2A (PP2A) are thought to cooperate as a dynamic signaling complex. In our prior work, adult rats have enhanced CA1 hippocampal long-term depression (LTD) following an early life seizure (ELS). We now show that mGluR-mediated LTD (mLTD) is specifically enhanced following ELS, similar to FMRP knock-outs. Total FMRP expression is unchanged but S6K is hyperphosphorylated, consistent with S6K overactivation. We postulated that either disruption of the FMRP–S6K–PP2A complex and/or removal of this complex from synapses could explain our findings. Using subcellular fractionation, we were surprised to find that concentrations of FMRP and PP2A were undisturbed in the synaptosomal compartment but reduced in parallel in the cytosolic compartment. Following ELS FMRP phosphorylation was reduced in the cytosolic compartment and increased in the synaptic compartment, in parallel with the compartmentalization of S6K activation. Furthermore, FMRP and PP2A remain bound following ELS. In contrast, the interaction of S6K with FMRP is reduced by ELS. Blockade of PP2A results in enhanced mLTD; this is occluded by ELS. This suggests a critical role for the location and function of the FMRP–S6K–PP2A signaling complex in limiting the amount of mLTD. Specifically, non-synaptic targeting and the function of the complex may influence the “set-point” for regulating mLTD. Consistent with this, striatal-enriched protein tyrosine phosphatase (STEP), an FMRP “target” which regulates mLTD expression, is specifically increased in the synaptosomal compartment following ELS. Further, we provide behavioral data to suggest that FMRP complex dysfunction may underlie altered socialization, a symptom associated and observed in other rodent models of autism, including FXS.

A chemical-genetics approach to study the molecular pathology of central serotonin abnormalities in fetal valproate syndrome

Valproate (VPA) is a commonly used drug worldwide despite increased awareness of its adverse effects, especially when used during pregnancy. Fetal valproate syndrome, characterised by birth defects, learning difficulties, and autism, is observed in up to 50% of children exposed in utero. The teratogenic properties of VPA are thought to result from altered gene expression through its inhibition of the chromatin modifying enzyme family of histone deacetylases (Hdac). Brainstem serotonergic abnormalities are believed to be important in mediating the behavioural manifestations of fetal valproate syndrome. Abnormal differentiation of these neurons has been reported in rodent models of autism and this syndrome. However, the role of Hdac and the identity of the salient genetic targets in VPA-associated serotonergic dysgenesis has not been determined; this has hampered the development of therapies that can ameliorate fetal valproate syndrome. Here we show that VPA specifically blocks serotonergic differentiation in a zebrafish model by downregulating the expression of the proneural gene, Ascl1b, which encodes a critical determinant of serotonergic fate. Using a chemical-genetics approach we show that VPA exposes cryptic transcriptional repression by tonic Notch signalling, which prevents the activation of Ascl1b. Chemical blockade of Notch signalling results in Ascl1b activation and the rescue of serotonergic differentiation in the presence of VPA. We find that the ability of VPA to silence Ascl1b and block serotonergic neurogenesis is specifically dependent on inhibition of Hdac1. Consistent with this finding, Hdac1 mutants fail to activate Ascl1b and lack 5-HT neurons. Moroever, treatment of Hdac1 mutants with a Notch inhibitor drug rescues 5-HT neurons, which confirms that Hdac1 mediates the effects of VPA. The current model of Hdac function proposes that cyclical Hdac activity is needed to prime active genes, such as Ascl1b, for further rounds of transcription. Our discovery of the interplay between chromatin modifiers and Notch in gene regulation adds a new layer of complexity to the epigenetic molecular model. Fetal valproate syndrome thus highlights the crucial role of the epigenetic interface in genome-environment interactions in disease. FundingUK Medical Research Council

Absence of social conditioned place preference in BTBR T+tf/J mice: Relevance for social motivation testing in rodent models of autism

A major goal of translation research in autism is to characterize the physiological and psychological processes underlying behavioral abnormalities. Since autism reflects impairments in social motivation, we modified the mouse three-chamber social approach apparatus for use as a social conditioned place preference arena. We paired one of two unique contexts with social interactions in juvenile mice for five or ten conditioning sessions in BTBR T+tf/J mice and a control strain with normal approach behaviors (C57BL/6J) since the BTBR T+tf/J inbred mouse strain displays a variety of behavioral alterations analogous to symptoms of autism spectrum disorders. While C57BL/6J mice formed a conditioned place preference to the context associated with social interactions, particularly those receiving ten days of conditioning, BTBR T+tf/J mice did not. Neither absence of social proximity nor avoidance due to high rates of autogrooming appeared to underlie the impaired positive incentive value of the unconditioned social stimulus in the BTBR T+tf/J strain. These data contribute to a growing body of evidence suggesting that the BTBR T+tf/J strain shows impairments in all diagnostic domains of autism including social motivation. Additionally, social conditioning testing might provide an important social motivation measure in other rodent models of neuropsychiatric disorders characterized by social abnormalities.

Emotional Empathy in Autism Spectrum Conditions: Weak, Intact, or Heightened?

Dear Editor, Autism spectrum conditions are frequently characterized as empathy disorders (e.g., Baron-Cohen and Wheelwright 2004; Decety and Moriguchi 2007). Although, thanks to the theory of mind hypothesis (Baron-Cohen 1995), it is widely accepted that people with autism tend to have weak cognitive empathy, there is now a range of theoretical views about autism and emotional empathy (EE). EE is an emotional response in an individual that stems from and parallels the emotional state of another individual. Theories positing (inter alia) that people with autism have weak EE include the ‘‘extreme male brain’’ theory (Baron-Cohen 2002) and the mirror neuron theory (Williams et al. 2001). In support of these theories, Minio-Paluello et al. (2009) reported that embodied pain empathy is absent in adults with Asperger syndrome. However, the video stimuli used in that study did not include facial, vocal, or gestural expressions of emotion. Other recent research indicates that people with Asperger syndrome have intact EE (Dziobek et al. 2008). Two theoretical approaches explicitly propose that individuals with autism actually have heightened EE: the ‘‘empathy imbalance’’ hypothesis (Smith 2006, 2009) and the ‘‘intense world’’ hypothesis (Markram et al. 2007). The former hypothesis is derived from a Darwinian argument about human empathy and the latter hypothesis is based on neurophysiological findings in a rodent model of autism. Both hypotheses propose that children with autism have overwhelming EE and thus find it difficult to interact with others. Houzel’s (2000) psychoanalytic approach also seems to imply that children with autism have too much EE. Caldwell (2006), an experienced autism practitioner, has outlined a similar idea. There is evidence that motor empathy (the tendency to automatically mimic the movements of another individual) and EE are inextricably linked (Nummenmaa et al. 2008). And there are now four empirical studies showing that people with autism spectrum conditions may have stronger EE/motor empathy than people with typical development. Capps et al. (1993) observed the faces of children with autism and children with typical development in a paradigm designed to elicit EE in the children. They found that the children with autism displayed much more empathic facial affect than the other children. Magnee et al. (2007) reported that the faces of adults with autism show heightened electromyographic responsiveness to the emotional expressions of others. Bird et al. (2007) found that adults with autism show heightened automatic mimicry of the hand movements of others. Bastiaansen et al. (2008) conducted a neuroimaging study in which the participants viewed movies of facial expressions of emotion: Adults with autism activated their neural mirror systems more strongly than participants with typical development. The researchers suggested that individuals with autism ‘‘may find the social world challenging not because it fails to engage them but because it overwhelms them’’ (p. 276). Many people with autism and their caregivers believe that heightened EE is a feature of autism (Smith 2009). The simplest (and most far-reaching) explanation of the origin of these beliefs is that they are accurate. I predict that further empirical evidence of heightened EE in individuals with autism will emerge. A. Smith (&) Dryburgh Industrial Estate, 7 Faraday Street, Dundee DD2 3QQ, Scotland, UK e-mail: adamjamessmith@fsmail.net