Valproic Acid Model Of Autism Research Articles

Pairing Tones with Vagus Nerve Stimulation Improves Brainstem Responses to Speech in the Valproic Acid Model of Autism.

Receptive language deficits and aberrant auditory processing are often observed in individuals with autism spectrum disorders (ASD). Symptoms associated with ASD are observed in rodents prenatally exposed to valproic acid (VPA), including deficits in speech sound discrimination ability. These perceptual difficulties are accompanied by changes in neural activity patterns. In both cortical and subcortical levels of the auditory pathway, VPA-exposed rats have impaired responses to speech sounds. Developing a method to improve these neural deficits throughout the auditory pathway is necessary. The purpose of this study was to investigate the ability of vagus nerve stimulation (VNS) paired with sounds to restore degraded inferior colliculus responses in VPA-exposed rats. VNS paired with the speech sound "dad" was presented to a group of VPA-exposed rats 300 times per day for 20 days. Another group of VPA-exposed rats were presented with VNS paired with multiple tone frequencies for 20 days. The inferior colliculus responses were recorded from 19 saline-exposed control rats, 18 VPA-exposed with no VNS, 8 VNS-speech paired VPA-exposed, and 7 VNS-tone paired VPA-exposed female and male rats. Pairing VNS with tones increased the IC response strength to speech sounds by 44% when compared to VPA-exposed rats alone. Contrarily, VNS-speech pairing significantly decreased the IC response to speech compared with VPA-exposed rats by 5%. The current research indicates that pairing VNS with tones improved sound processing in rats exposed to VPA and suggests that auditory processing can be improved through targeted plasticity.

The neuroprotective effect of Diosgenin in the rat Valproic acid model of autism

Background and aimAutism spectrum disorder (ASD) is a neurodevelopmental disorder with two core behavioral symptoms restricted/repetitive behavior and social-communication deficit. The unknown etiology of ASD makes it difficult to identify potential treatments. Valproic acid (VPA) is an anticonvulsant drug with teratogenic effects during pregnancy in humans and rodents. Prenatal exposure to VPA induces autism-like behavior in both humans and rodents. This study aimed to investigate the protective effects of Diosgenin in prenatal Valproic acid-induced autism in rats. Methodpregnant Wister female rats were given a single intraperitoneal injection of VPA (600 mg/kg, i.p.) on gestational day 12.5. The male offspring were given oral Dios (40 mg/kg, p.o.) or Carboxymethyl cellulose (5 mg/kg, p.o.) for 30 days starting from postnatal day 23. On postnatal day 52, behavioral tests were done. Additionally, biochemical assessments for oxidative stress markers were carried out on postnatal day 60. Further, histological evaluations were performed on the prefrontal tissue by Nissl staining and Immunohistofluorescence. ResultsThe VPA-exposed rats showed increased anxiety-like behavior in the elevated plus maze (EPM). They also demonstrated repetitive and grooming behaviors in the marble burying test (MBT) and self-grooming test. Social interaction was reduced, and they had difficulty detecting the novel object in the novel object recognition (NOR) test. Also, VPA-treated rats have shown higher levels of oxidative stress malondialdehyde (MDA) and lower GPX, TAC, and superoxide dismutase (SOD) levels. Furthermore, the number of neurons decreased and the ERK signaling pathway upregulated in the prefrontal cortex (PFC). On the other hand, treatment with Dios restored the behavioral consequences, lowered oxidative stress, and death of neurons, and rescued the overly activated ERK1/2 signaling in the prefrontal cortex. ConclusionChronic treatment with Dios restored the behavioral, biochemical, and histological abnormalities caused by prenatal VPA exposure.

Region-Specific Brain Volume Changes Emerge in Adolescence in the Valproic Acid Model of Autism and Parallel Human Findings

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, cognitive dysfunction, and stereotyped repetitive behaviors. Regional volume changes are commonly observed in individuals with ASD. To examine volumetric dysregulation across adolescence, the valproic acid (VPA) model was used to induce ASD-like phenotypes in rats. Method: Regional volumes were obtained via magnetic resonance imaging at either postnatal day 28 or postnatal day 40 (P40), which correspond to early and late adolescence, respectively. Results: Consistent with prior research, VPA animals had reduced total brain volume compared to control animals. A novel outcome was that VPA animals had overgrown right hippocampi at P40. Differences in the pattern of development of the anterior cingulate cortex were also observed in VPA animals. Differences for the posterior cingulate were only observed in males, but not females. Conclusion: These results demonstrate differences in region-specific developmental trajectories between control and VPA animals and suggest that the VPA model may capture regional volume changes consistent with human ASD.

The role of the CNTNAP2 gene in the development of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which genetic and environmental factors interact in its development. Research suggests that the contactin associated protein 2 (CNTNAP2) gene may play a role in ASD pathophysiology, yet more studies involving human participants and animal models of autism are needed. One such model may be the use of prenatal valproic acid (VPA) model to induce autism-like behaviors in offspring rats. The aim of this study was twofold: (1) to examine the association of the CNTNAP2 gene rs2710102 variant with ASD in children; and (2) to examine the effect of prenatal exposure to VPA on Cntnap2 gene expression in the rat brain. The study included 167 children of European ancestry—81 diagnosed with ASD (20 girls, 61 boys; age 4.9 ± 1.4 years) and 86 controls (44 girls, 42 boys; 5.1 ± 1.2 years). In vivo experiments were conducted in 80 rats (40 with the VPA model of autism), with Cntnap2 gene expression analysis in the amygdala, hippocampus, prefrontal cortex, and cerebellum. Results demonstrated that the frequency of the CNTNAP2 gene rs2710102 GG genotype was significantly higher in children with ASD when compared with controls (33.3 vs 19.8%; OR=2.03, 95%CI [1.004, 4.102], p = 0.035), although, potentially due to bias in cohort selection, in the ASD children this polymorphism did not meet Hardy-Weinberg expectations (χ2 =5.40, p = 0.02). In addition, Cntnap2 gene expression was significantly lower (p < 0.01) in the amygdala and hippocampus of VPA rats when compared with controls, regardless of sex. These results support previous research and provide evidence for the CNTNAP2 gene as a risk factor for ASD.

Independent and combined effects of astaxanthin and omega-3 on behavioral deficits and molecular changes in a prenatal valproic acid model of autism in rats

ABSTRACT Objectives: Autism is a devastating neurodevelopmental disorder and recent studies showed that omega-3 or astaxanthin might reduce autistic symptoms due to their anti-inflammatory properties. Therefore, we investigated the effects of omega-3 and astaxanthin on the VPA-induced autism model of rats. Material and Methods : Female Wistar albino pups (n = 40) were grouped as control, autistic, astaxanthin (2 mg/kg), omega-3 (200 mg/kg), and astaxanthin (2 mg/kg)+omega-3 (200 mg/kg). All groups except the control were prenatally exposed to VPA. Astaxanthin and omega-3 were orally administered from the postnatal day 41 to 68 and behavioral tests were performed between day 69 and 73. The rats were decapitated 24 h after the behavioral tests and hippocampal and prefrontal cytokines and 5-HT levels were analyzed by ELISA. Results: VPA rats have increased grooming behavior while decreased sociability (SI), social preference index (SPI), discrimination index (DI), and prepulse inhibition (PPI) compared to control. Additionally, IL-1β, IL-6, TNF-α, and IFN-γ levels increased while IL-10 and 5-HT levels decreased in both brain regions. Astaxanthin treatment raised SI, SPI, DI, PPI, and prefrontal IL-10 levels. It also raised 5-HT levels and decreased IL-6 levels in both brain regions. Omega-3 and astaxanthin + omega-3 increased the SI, SPI, DI, and PPI and decreased grooming behavior. Moreover, they increased IL-10 and 5-HT levels whereas decreased IL-1β, IL-6, TNF-α, IFN-γ levels in both brain regions. Conclusions: Our results showed that VPA administration mimicked the behavioral and molecular changes of autism in rats. Single and combined administration of astaxanthin and omega-3 improved the autistic-like behavioral and molecular changes in the VPA model of rats.

Effects of different doses of lithium on the central nervous system in the rat valproic acid model of autism

Epidemiological studies have shown that low doses of lithium in the environment can have beneficial effects on mental health. Autism spectrum disorder, a neurodevelopmental disorder in which patients exhibit abnormal behaviors, pharmacological interventions usually relied on a range of psychotropic medications. However, such medications often produce severe side effects or are ineffective in symptoms. Finding alternative ways to improve abnormal behaviors in individuals with autism are warranted, in which case lithium may be a relatively safe and effective medication. Lithium salt therapy is used to treat a variety of neuropsychiatric disorders and has neuroprotective effects. In this study, we investigated the effects of different doses of lithium on neurobehavioural disorders using the rat model of autism established by valproic acid (VPA) injection. Lithium was observed to have an ameliorative effect on the social cognitive, social memory and anxiety levels in the rat model of autism. Immunofluorescence staining showed that subchronic LiCl administration (1.0 mmol/kg) significantly reduced the number of Iba-1 positive cells in the CA1 region of the hippocampus in VPA group and brought it close to the levels of control group. Significantly lower levels of the pro-inflammatory marker IL-6 were observed in the hippocampus and serum after lithium treatment. In addition, the lithium treatment increased the levels of H3K9 acetylation in the hippocampus of VPA-exposed rats. The results showed a defensive effect of environment-related lithium exposure doses on neurobehavioural deficits in the rat valproic acid model of autism, suggesting that it may be a potential drug for the treatment of autism.

Increased volumes of lobule VI in a valproic acid model of autism are associated with worse set-shifting performance in male Long-Evan rats

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a skewed sex-based diagnostic ratio. While males are at a higher risk for ASD, it is critical to understand the neurobiology of the disorder to develop better treatments for both males and females. Our prior work has demonstrated that VPA (valproic acid) treated offspring had impaired performance on an attentional set-shifting task. The current study used MRI and regions of interest analyses to measure the volumes of cerebellar subregions in VPA and controls rats that had participated in the attentional set-shifting task. VPA males had significantly more volume in lobule VI compared to male controls. VPA female rats had significantly less volume in lobules I, IV and X compared to female controls. In addition, it was revealed that decreases in volume for VPA females was associated with worse performance. Males with increases in lobule VI were also impaired on the set-shifting task. Similar volumetric differences within the cerebellum have been observed in humans with ASD, which suggests that the VPA model is capturing some of the same brain changes observed in humans with ASD, and that these changes in volume may be impacting cognition.

Valproic acid treated female Long-Evans rats are impaired on attentional set-shifting

Autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by social deficits, communication impairments, restrictive behaviors, and cognitive flexibility deficits. The valproic acid (VPA) model of autism has been widely used to examine changes in rodent behavior and neurobiology to better understand ASD. This study examined social and anxiety behavior as well as cognitive flexibility in VPA and control offspring. Results for social behavior were consistent with prior studies showing reduced sociability in VPA rats and increased self-grooming, which may be viewed as a repetitive behavior. VPA rats also had deficits in performing the set-shifting task, with female VPA rats demonstrating greater impairment compared to female control rats and male VPA rats. These results support the hypothesis that females diagnosed with ASD may suffer from different symptoms and present a unique behavioral profile compared to males with ASD. Female VPA rats were also less likely to form an attentional set; offering evidence that the VPA model of autism is encompassing executive function deficits similar to those observed in humans with ASD.

Targeting PPAR\u03b1 in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences

BackgroundThe social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments.MethodsMale and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48–53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D1 receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions.ResultsFBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D1 receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment.LimitationsThis study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue.ConclusionsThe results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment.

Potentiation of Glutamatergic Synaptic Transmission Onto Dorsal Raphe Serotonergic Neurons in the Valproic Acid Model of Autism.

Autism spectrum disorder (ASD) is characterized by social and communicative impairments and increased repetitive behaviors. These symptoms are often comorbid with increased anxiety. Prenatal exposure to valproic acid (VPA), an anti-seizure and mood stabilizer medication, is a major environmental risk factor of ASD. Given the important role of the serotonergic (5-HT) system in anxiety, we examined the impact of prenatal VPA exposure on the function of dorsal raphe nucleus (DRn) 5-HT neurons. We found that male rats prenatally exposed to VPA exhibited increased anxiety-like behaviors revealed by a decreased time spent on the open arms of the elevated plus maze. Prenatal VPA exposed rats also exhibited a stereotypic behavior as indicated by excessive self-grooming in a novel environment. These behavioral phenotypes were associated with increased electrical activity of putative DRn 5-HT neurons recorded in vitro. Examination of underlying mechanisms revealed that prenatal VPA exposure increased excitation/inhibition ratio in synapses onto these neurons. The effect was mainly mediated by enhanced glutamate but not GABA release. We found reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs) and increased frequency but not amplitude of miniature EPSCs in VPA exposed rats. On the other hand, presynaptic GABA release did not change in VPA exposed rats, as the PPR of evoked inhibitory postsynaptic currents was unaltered. Furthermore, the spike-timing-dependent long-term potentiation at the glutamatergic synapses was occluded, indicating glutamatergic synaptic transmission is maximized. Lastly, VPA exposure did not alter the intrinsic membrane properties of DRn 5-HT neurons. Taken together, these results indicate that prenatal VPA exposure profoundly enhances glutamatergic synaptic transmission in the DRn and increases spontaneous firing in DRn 5-HT neurons, which could lead to increased serotonergic tone and underlie the increased anxiety and stereotypy after prenatal VPA exposure.

P.1.h.002 - Role of the endocannabinoid system in the altered social behavior observed in the rat valproic acid model of autism

Mood disorders such as depression and anxiety are frequently observed in patients suffering from chronic pain, including neuropathic pain. While this comorbidity is clinically well established, the underlying mechanism(s) remained unclear. The recent development of animal models now allows addressing the consequences of neuropathic pain. In this review, we report the preclinical evidences from anatomical, neuroimaging, behavioral, pharmacological and biochemical studies that address the anxiodepressive consequences of neuropathic pain. We present an overview of rodent models of these consequences and we discuss the challenges and parameters to consider for generating these models. We then discuss the possible mechanism(s) underlying anxiodepressive consequences by describing morphological and functional changes. Information is provided concerning neuroanatomical changes and plasticity, including LTP and LTD, in the anterior cingulate cortex, the insula, the hippocampus, the amygdala and the mesolimbic system, neuroendocrine parameters concerning the hypothalamo-pituitary-adrenal axis, neuroimmune response including the role of glial cells and cytokines, monoamine systems and changes in locus coeruleus noradrenergic system, and neurotrophic factors such as BDNF.

Increased expression of fatty acid synthase and acetyl-CoA carboxylase in the prefrontal cortex and cerebellum in the valproic acid model of autism.

The primary aim of the present study was to investigate alterations in enzymes associated with fatty acid synthesis, namely fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), in the prefrontal cortex and cerebellum of the valproic acid (VPA)-induced animal model of autism. In this model, pregnant rats were given a single intraperitoneal injection of VPA, and prefrontal cortex and cerebellum samples from their pups were analyzed. The results of western blotting and reverse transcription-quantitative polymerase chain reaction analyses demonstrated that the protein and mRNA expression levels of FASN, ACC and phospho-ACC (pACC) were increased in the prefrontal cortex and cerebellum of the VPA model of autism. Furthermore, in the prefrontal cortex and cerebellum of the VPA model of autism, AMPK expression is increased, whereas PI3K and Akt expression are unchanged. This suggests that disorder of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt/FASN and/or adenosine 5′-monophosphate-activated protein kinase (AMPK)/ACC pathway may be involved in the pathogenesis of autism. It is hypothesized that fatty acid synthesis participates in autism through PI3K/Akt/FASN and AMPK/ACC pathways.

Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data.

Increased BDNF expression in fetal brain in the valproic acid model of autism

Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: Comparison with valproic acid autistic model

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800mg/kg b.wt) at the 12.5days of gestation. Butyl paraben was orally and subcutaneously administered (200mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism.

Alterations in the endocannabinoid system in the rat valproic acid model of autism

The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders.

MGluR5-Antagonist Mediated Reversal of Elevated Stereotyped, Repetitive Behaviors in the VPA Model of Autism

Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1–3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism.