Mouse Model Of Autism Research Articles

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology was studied in the prefrontal cortex of 60 days old male and female mice using the NanoString nCounter. In females, VPA induced statistically significant changes in the expression of 146 genes; 71 genes were upregulated and 75 downregulated. In males, VPA changed the expression of only 19 genes, 16 were upregulated and 3 downregulated. Eight genes were similarly changed in both genders. When considering only the genes that were changed by at least 50%, VPA changed the expression of 15 genes in females and 3 in males. Only Nts was similarly downregulated in both genders. SAM normalized the expression of most changed genes in both genders. We presume that genes that are involved in autism like behavior in our model were similarly changed in both genders and corrected by SAM. The behavioral and other differences between genders may be related to genes that were differently affected by VPA in males and females and/or differently affected by SAM.

Gene network analysis reveals a role for striatal glutamatergic receptors in dysregulated risk-assessment behavior of autism mouse models

Autism spectrum disorder (ASD) presents a wide, and often varied, behavioral phenotype. Improper assessment of risks has been reported among individuals diagnosed with ASD. Improper assessment of risks may lead to increased accidents and self-injury, also reported among individuals diagnosed with ASD. However, there is little knowledge of the molecular underpinnings of the impaired risk-assessment phenotype. In this study, we have identified impaired risk-assessment activity in multiple male ASD mouse models. By performing network-based analysis of striatal whole transcriptome data from each of these ASD models, we have identified a cluster of glutamate receptor-associated genes that correlate with the risk-assessment phenotype. Furthermore, pharmacological inhibition of striatal glutamatergic receptors was able to mimic the dysregulation in risk-assessment. Therefore, this study has identified a molecular mechanism that may underlie risk-assessment dysregulation in ASD.

Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism

BTBR T + Itpr3tf/J (BTBR) mice are an Autism Spectrum Disorder (ASD)-like model that exhibit behavioral and physiological deficits similar to those observed in patients with ASD. While behavioral therapy is a first line of treatment in ASD patients, comparable non-pharmacological treatments are less explored in murine models. Here, we administer a bio-behavioral intervention for BTBR mice by way of environmental enrichment (EE) — an experimental housing paradigm previously shown to improve systemic metabolism, learning/memory, anxious behavior, neurogenesis, locomotion, and immunocompetence in C57BL/6 mice. Juvenile BTBR mice were randomized to standard or EE housing and were subjected to metabolic and behavioral assessments up to 17 weeks. Following EE exposure, we report an EE-induced metabolic and behavioral phenotype. Male BTBR mice responded metabolically to EE, displaying reduced adiposity, increased lean mass, improved glycemic control, and decreased circulating leptin. The gene expressions of brain-derived neurotrophic factor (Bdnf) and its receptor (Ntrk2/TrkB) were upregulated in several brain areas in EE-BTBR males. EE-BTBR females showed modest reduction of adiposity and no changes in glycemic control, circulating leptin, or Bdnf/Ntrk2 gene expression. With regard to behavior, EE resulted in decreased anxiety, and increased social affiliation. Together, these results suggest that EE improves metabolic and behavioral health in BTBR mice.

Precocious myelination in a mouse model of autism

Autism spectrum disorder (ASD) has been hypothesized to be a result of altered connectivity in the brain. Recent imaging studies suggest accelerated maturation of the white matter in young children with ASD, with underlying mechanisms unknown. Myelin is an integral part of the white matter and critical for connectivity; however, its role in ASD remains largely unclear. Here, we investigated myelin development in a model of idiopathic ASD, the BTBR mice. Magnetic resonance imaging revealed that fiber tracts in the frontal brain of the BTBR mice had increased volume at postnatal day 6, but the difference reduced over time, reminiscent of the findings in young patients. We further identified that myelination in the frontal brain of both male and female neonatal BTBR mice was increased, associated with elevated levels of myelin basic protein. However, myelin pattern was unaltered in adult BTBR mice, revealing accelerated developmental trajectory of myelination. Consistently, we found that signaling of platelet-derived growth factor receptor alpha (PDGFRα) was reduced in the frontal brain of neonatal BTBR mice. However, levels of microRNA species known to regulate PDGFRα signaling and myelination were unaltered. Together, these results suggest that precocious myelination could potentially contribute to increased volume and connectivity of the white matter observed in young children with ASD.

Sex-specific alterations in behavior and neuroinflammation in a mouse model of autism

Sex-specific alterations in behavior and neuroinflammation in a mouse model of autism

Early correction of NMDA receptor dysfunction in mouse models of autism

Early correction of NMDA receptor dysfunction in mouse models of autism

Tipping excitation/inhibition balance in autism mouse models

Tipping excitation/inhibition balance in autism mouse models

Erratum: Soda et al., "Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism".

Erratum: Soda et al., "Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism".

Interneuron Transplantation Creates New Network States and Rescues Social Behavior Deficits in a Mouse Model of Autism

Abstract INTRODUCTION Inhibitory interneuron transplantation is a prospective treatment for neuropsychiatric disorders, but it is unclear whether transplantation might elicit therapeutic effects by reversing preexisting abnormalities, nonspecifically increasing synaptic inhibition, or engaging mechanisms that vary depending on recipient background and behavioral state. METHODS We transplanted wild-type embryonic interneuron precursors into mice lacking an autism-associated gene, Pten, in inhibitory interneurons. Additionally, we performed transplantation into wild-type recipient mice, and then examined the recipient behavior, cellular physiology in Vitro, and network physiology in Vivo. RESULTS Transplantation rescued social behavior deficits in Pten mutants without normalizing excessive synaptic inhibition in Vitro or reduced baseline gamma oscillatory power in Vivo. However, transplantation altered recipient electroencephalography (EEG) responses observed specifically during periods of social interaction. When transplantation was performed into wild-type recipients, the subtype composition of the transplanted population varied from that observed in Pten mutants, and, moreover, recipients did not exhibit alterations to social behavior or related EEG responses. CONCLUSION Interneuron transplantation elicits recipient- and behavioral state-dependent effects, and normalizes behavior by creating new patterns of network activity, rather than restoring wild-type states. Interneuron transplantation may provide a novel therapeutic approach to the treatment of autism and related neuropsychiatric disorders.

Gene-environment interaction counterbalances social impairment in mouse models of autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive/restricted behaviors. Although gene-environment interactions may explain the heterogeneous etiology of ASD, it is still largely unknown how the gene-environment interaction affects behavioral symptoms and pathophysiology in ASD. To address these questions, we used Cntnap2 knockout mice (genetic factor, G) exposed to valproic acid during embryonic development (environmental factor, E) as a gene-environment interaction (G × E) model. Paradoxically, the social deficits observed in the respective G and E models were improved in the G × E model; however, the high seizure susceptibility was more severe in the G × E -model than in the G and E models. Repetitive self-grooming and hyperactivity did not differ among the three models. The amplitudes of miniature excitatory postsynaptic currents in layer 2/3 pyramidal neurons of the medial prefrontal cortex were aberrant and similar in the G × E model when compared to the control group. Our findings suggest that the interaction of two risk factors does not always aggravate ASD symptoms but can also alleviate them, which may be key to understanding individual differences in behavioral phenotypes and symptom intensity.

Impaired approach to novelty and striatal alterations in the oxytocin receptor deficient mouse model of autism

Long-standing studies established a role for the oxytocin system in social behavior, social reward, pair bonding and affiliation. Oxytocin receptors, implicated in pathological conditions affecting the social sphere such as autism spectrum disorders, can also modulate cognitive processes, an aspect generally overlooked.Here we examined the effect of acute (pharmacological) or genetic (Oxtr−/−) inactivation of oxytocin receptor-mediated signaling, in male mice, in several cognitive tests. In the novel object recognition test, both oxytocin receptor antagonist treated wild type animals and Oxtr−/− mice lacked the typical preference for novelty. Oxtr−/− mice even preferred the familiar object; moreover, their performance in the Morris water maze did not differ from wild types, suggesting that oxytocin receptor inactivation did not disrupt learning. Because the preference for novel objects could be rescued in Oxtr−/− mice with longer habituation periods, we propose that the loss of novelty preferences following Oxtr inactivation is due to altered processing of novel contextual information.Finally, we observed an increased expression of excitatory synaptic markers in the striatum of Oxtr−/− mice and a greater arborization and higher number of spines/neuron in the dorsolateral area of this structure, which drives habit formation. Our data also indicate a specific reshaping of dorsolateral striatal spines in Oxtr−/− mice after exposure to a novel environment, which might subtend their altered approach to novelty, and support previous work pointing at this structure as an important substrate for autistic behaviors.

The Stat3 inhibitor, S3I-201, downregulates lymphocyte activation markers, chemokine receptors, and inflammatory cytokines in the BTBR T+ Itpr3tf/J mouse model of autism

Autism is a complex neurodevelopmental disorder with a high incidence rate. It is characterized by deficits in communication, a lack of social skills, cognitive inflexibility, and stereotypical behaviors. Autism has been gradually increasing in children over the past several years, without the existence of an effective treatment. BTBR T+ Itpr3tf/J (BTBR) mice serve as an accepted model to evaluate autistic-like behaviors as they display core behavioral symptoms displayed in autism. Previous findings showed that S3I-201, a selective Stat3 inhibitor, can be used to treat neuroinflammation disorders. Previously, we showed that S3I-201 treatment has therapeutic effects on autism-like behaviors, and Th1/Th17 and regulatory T cells in BTBR mice. The objective of the present study was to further explore the role of S3I-201 in BTBR mice, and this was performed by investigating the effects of S3I-201 treatment on lymphocyte activation markers (CD4+CD25+ and CD4+CD69+), chemokine receptors (CD4+CCR6+, CD4+CCR7+, CD4+CXCR4+, and CD4+CXCR5+), and proinflammatory cytokines (CD4+IL-6+ and CD4+TNF-α+) in the spleen cells of BTBR and C57BL/6 (C57) mice. The mRNA and protein expression levels of CD69, CCR6, CCR7, CXCR4, CXCR5, IL-1β, IL-6, and TNF-α were examined in the brain tissues, and in BTBR mice, a significant decrease in CD25, CD69, CCR6, CCR7, CXCR4, CXCR5, IL-6, and TNF-α producing CD4+ T cells was observed. The present findings suggest that treatment with S3I-201 may be a therapeutic approach to improve immune abnormalities in a subgroup of autistic subjects.

Brain Dynamics: Global Pulse and Brain State Switching

A major challenge in systems-level neuroscience is to understand the dynamic formation and succession of brain states. A new study has extracted reproducible brain states from mouse resting-state fMRI data, revealing interactions between occurrences of these states and the phase of global signal fluctuations and alterations of the states in a mouse model of autism.

Improvement of a mouse model of valproic acid-induced autism

To establish an improved mouse model of valproic acid (VPA)-induced autism that better mimics human autism. We established mouse models of autism in female C57 mice by intraperitoneal injection of sodium valproate either at a single dose (600 mg/kg) on day 12.5 after conception (conventional group) or in two doses of 300 mg/kg each on days 10 and 12 after conception (modified group), and the control mice were injected with saline only on day 12.5. The responses of the mice to VPA injection, the uterus, mortality rate, and abortion rate were compared among the 3 groups. The morphology and development of the offspring mice were assessed, and their behavioral ontogeny was evaluated using 3- chambered social test, social test, juvenil play test, and open field test. The mortality and abortion rates were significantly lower in the modified model group than in the conventional group (P < 0.01). Compared with those in the control group, the offspring mice in both the conventional group and the modified group showed developmental disorders (P < 0.05). The mortality rate of the newborn mice was significantly lower in the modified group than in the conventional group with a rate of curvy tail of up to 100% (P < 0.001). The offspring mice in both the modified group and conventional group exhibited autism-like behavioral abnormalities, including social disorder and repetitive stereotyped behavior (P < 0.05). The mouse model of autism established using the modified method better mimics human autism with reduced mortality and abortion rates of the pregnant mice and also decreased mortality rate of the newborn mice.

Folic acid improves abnormal behavior via mitigation of oxidative stress, inflammation, and ferroptosis in the BTBR T+ tf/J mouse model of autism

The aim of this study was to examine the effects of folic acid (FA) on the autistic phenotypes in BTBR T+ Itpr3tf/J (BTBR) mice and to investigate underlying mechanisms. Mice received FA (0.2 mg/kg/day) orally from postnatal days 14 to 35. Mice were then tested for stereotyped and repetitive behaviors, social interaction, and spatial learning and memory at the end of FA supplementation. Oxidative stress, neuroinflammatory responses and ferroptosis-related proteins in the brain were also evaluated. FA supplementation in BTBR mice reduced repetitive and stereotyped behavior, improved social communication, and enhanced memory and spatial learning. FA supplementation also reduced neuronal loss in hippocampal CA1 regions of the brain and decreased the levels of the proinflammatory cytokines such as interleukin-1β (IL-1β), Iba-1, IL-18, tumor necrosis factor-a, and IL-6 and glial fibrillary acidic protein in the hippocampus. FA supplementation changed the malondialdehyde and glutathione levels and superoxide dismutase (SOD) and glutathione peroxidase activities in the hippocampus. FA supplementation inhibited the elevation of the SOD1 and TFR protein levels and enhanced the relative expression levels of glutathione peroxidase 4 and ferroportin 1 in the hippocampus and increased the relative levels of phospho-Ca2+/calmodulin-dependent protein kinase II and phospho-cAMP-response element binding protein in the hippocampus. FA oral supplementation to BTBR mice rescued stereotyped and repetitive behaviors, social deficit, and spatial learning and memory impairments, likely by improving the oxidative-stress and inflammatory responses by altering the ferroptosis signaling pathways.

The critical role of vestibular graviception during cognitive-motor development

Earth’s gravity acts both as a mechanical stimulus on the body and as a sensory stimulus to the vestibular organ, which is transmitted into the brain. The vestibular system has been recently highlighted as the cornerstone of the multisensory cortex and of the dorsal hippocampus related to spatial cognition. Consequently, we have hypothesized that the vestibular sensory perception of gravity by the otoliths might also play a crucial role during the first stages of development in both sensorimotor and cognitive functions and the construction and perception of the ‘self’ and related functions of orientation and navigation. We have investigated an original mouse model (Head Tilted mice, B6Ei.GL-Nox3het/J) suffering from a selective congenital absence of vestibular otolithic gravisensors. We report that mouse pups suffered from a delay in the acquisition of sensorimotor reflexes, spatial olfactory guidance, path integration, and ultrasonic communication, while maternal care remained normal. We demonstrate that development has a critical period dependent on the vestibular otolithic sensory perception of gravity, probably temporally between the somesthetic and visual critical periods. The symptoms expressed by the congenital otolithic-deficient mice are similar to validated mouse models of autism and highlight the significance of vestibular graviception in the pathophysiology of development.

Rubber tail illusion is weakened in Ca2+-dependent activator protein for secretion 2 (Caps2)-knockout mice

Body ownership is a fundamental aspect of self-consciousness. Illusion of body ownership is caused by updating body representation through multisensory integration. Synchronous visuotactile stimulation of a hand and rubber hand leads to illusory changes in body ownership in humans, but this is impaired in individuals with autism spectrum disorder (ASD). We previously reported that mice also exhibit body ownership illusion. With synchronous stroking of a tail and rubber tail, mice responded as if their own tails were being touched when the rubber tails were grasped (‘rubber tail illusion’). However, it remains unknown whether deficits in illusion of body ownership occur in mouse models of autism. Here, we examined whether the ‘rubber tail illusion’ occurred in Ca2+-dependent activator protein for secretion 2-knockout (Caps2-KO) mice, which exhibit autistic-like phenotypes. During the synchronous stroking, response rates were significantly lower in Caps2-KO mice than in wild-type mice. There were no significant differences between the response rates of wild-type and Caps2-KO mice during the asynchronous stroking. The ‘rubber tail illusion’ was weak in Caps2-KO mice, suggesting that Caps2-KO mice experienced weaker visuotactile integration during the task. The rubber tail task will be a useful tool in mouse models of autism to evaluate atypical sensory processing.

The Liver X Receptor Agonist TO901317 Ameliorates Behavioral Deficits in Two Mouse Models of Autism.

Autism spectrum disorder (ASD) is a developmental disability characterized by social deficits and repetitive stereotyped behaviors. There are currently no drugs available for the treatment of the core symptoms of ASD, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but emerging research indicates that defects in hippocampal neurogenesis are associated with ASD in both humans and mouse models of ASD, leading to the suggestion that restoring neurogenesis may be a novel therapeutic approach for ASD. Here, we found that postnatal treatment with TO901317 (TO), a potent liver X receptor (LXR) agonist, typically activated LXRβ and its target genes in the hippocampus, and alleviated the social deficits and stereotypical behaviors in BTBR T+ tf/J (BTBR) and valproic acid (VPA)-induced mouse models. In addition, we further confirmed that TO postnatal treatment also rescued the inhibition of adult hippocampal neurogenesis in these two models. In summary, our study suggests that LXR agonist targeting hippocampal neurogenesis may represent a novel potential therapy for ASD.

Citalopram attenuates social behavior deficits in the BTBR T+Itpr3tf/J mouse model of autism

Autism spectrum disorder (ASD) is diagnosed by two core symptoms: impaired social communication and the presence of repetitive, stereotyped behaviors and/or restricted interests. Alterations in serotonergic signaling are involved in the genesis of ASD. Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce repetitive behaviors and rescue social deficits in ASD mouse models and patients. In the present study, we examined the potential of citalopram (a representative selective serotonin reuptake inhibitor) on sociability and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of ASD. We found that the deficits of sociability in the BTBR mice were reversed by a 20 mg/kg dose of citalopram treatment without any adverse effects on locomotor activity or anxiety level. In addition, both high (20 mg/kg) and low (10 mg/kg) doses decreased the repetitive behavior of marble burying but did not affect self-grooming behavior. Furthermore, both doses were shown to have antidepressant-like activity in both the B6 and the BTBR mice in the tail suspension test. Taken together, these findings further demonstrate that citalopram can alleviate behavioral abnormalities in the BTBR autism model and lend support to the hypothesis that SSRIs may be potential therapeutic drugs for the treatment of behavioral dysfunctions in ASD.

Betaine ameliorates prenatal valproic-acid-induced autism-like behavioral abnormalities in mice by promoting homocysteine metabolism.

Abnormally high levels of homocysteine (Hcy) are associated with autism spectrum disorder. Betaine is a methyl group donor in Hcy metabolism, and is known to prevent noxious Hcy accumulation. This study explored whether betaine could influence Hcy metabolism in a mouse model of autism and ameliorate behavioral abnormalities. Pregnant ICR mice were administered valproic acid (VPA) intraperitoneally on Embryonic Day 12.5. Serum Hcy concentrations in the offspring were measured by enzyme-linked immunosorbent assay. Expressions of Hcy-metabolism-related enzymes, betaine-Hcy methyltransferase, cystathionine β-synthase, and methionine synthase, were measured by quantitative reverse transcription polymerase chain reaction and western blotting. Offspring were treated by either betaine or saline at the age of 8 weeks and serum Hcy concentrations were measured. Social behaviors were assessed by sniff-duration test and three-chamber test. Repetitive behavior was evaluated by marble-burying test. Tail-flick test was performed to measure nociceptive sensitivity. Prenatal VPA-exposed mice showed significantly elevated Hcy concentrations and decreased betaine-Hcy methyltransferase expression. Treatment with betaine could reduce Hcy level in VPA-exposed mice, attenuate social impairment and repetitive behavior, and normalize nociceptive sensitivity in this model. Betaine could ameliorate autism-like features and play a beneficial role in a mouse autism model induced by prenatal VPA exposure.