1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alzahrani MZ, Alshammari MA, Alanazi WA, Alasmari AF, Attia SM. {{Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T(+) Itpr3(tf)/J autistic mice}}. {European journal of pharmacology}. 2018; 829: 70-8.
Autism is a neurodevelopmental disorder characterized by qualitative impairment in communication, social interaction, and repetitive stereotypic behavior. Resveratrol plays a role in several disorders such as neuroimmune, autoimmune, and allergic disorders. BTBR T(+) Itpr3(tf)/J (BTBR) mice, a model for autism, show several behavioral deficits that are physiological characteristics similar to those observed in patients with autism. Previous studies have shown that JAK-STAT signaling pathway is associated with many neurodevelopmental disorders. We investigated the possible role of resveratrol on IL-6(+), TNF-alpha(+), IFN-gamma(+), and STAT3(+) in CD4(+) T spleen cells in BTBR mice as compared to C57BL/6J mice. We also assessed the effect of resveratrol treatment on IL-6, TNF-alpha, IFN-gamma, JAK1, and STAT3 mRNA expression levels in the brain tissue. We further assessed IL-6, IFN-gamma, TNF-alpha, phosphorylated (p) JAK1, and pSTAT3 (Tyr705) protein expression levels in the brain tissue. Resveratrol (20 and 40mg/kg)-treated mice had significantly decreased in IL-6(+), TNF-alpha(+), IFN-gamma(+), and STAT3(+) in CD4(+) spleen cells as compared with BTBR control mice. Resveratrol treatment also decreased IL-6, TNF-alpha, IFN-gamma, JAK1, and STAT3 mRNA expression levels as compared with BTBR control mice in the brain tissue. Moreover, resveratrol treatment resulted in decreased protein expression levels of IL-6, IFN-gamma, TNF-alpha, pJAK1, and pSTAT3 (Tyr705) as compared with BTBR control mice in the brain tissues. Taken together, these results indicate the efficacy of resveratrol in reducing cytokines and JAK-1/STAT3 signaling in BTBR mice, which is a novel and important finding and might be important for future therapies in neuroimmune dysfunction.
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2. Bjorklund G, Skalny AV, Rahman MM, Dadar M, Yassa HA, Aaseth J, Chirumbolo S, Skalnaya MG, Tinkov AA. {{Toxic metal(loid)-based pollutants and their possible role in autism spectrum disorder}}. {Environmental research}. 2018; 166: 234-50.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-kappaB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects’ genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies.
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3. Frazier TW, Dawson G, Murray D, Shih A, Sachs JS, Geiger A. {{Brief Report: A Survey of Autism Research Priorities Across a Diverse Community of Stakeholders}}. {J Autism Dev Disord}. 2018.
Inclusion of stakeholder voices in the allocation of research funding can increase the relevance of results and improve community engagement in research. We describe the results of an online survey that gathered input from community stakeholders regarding autism research priorities. A demographically diverse sample of respondents (N = 6004; 79.1% female; 72.5% ages 30-59; 86.4% USA) completed the survey. Results indicated a preference for applied relative to basic science topics, though both basic and applied science areas were rated as important. Respondents gave their highest ratings to research focused on co-occurring conditions, health and well-being, adult transition, and lifespan issues. These results can guide decision-making by public and private funders when developing science funding priorities and engaging in science dissemination activities.
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4. Hamm J, Yun J. {{The motivational process for physical activity in young adults with autism spectrum disorder}}. {Disability and health journal}. 2018.
BACKGROUND: Many young adults, specifically those with a diagnosis of autism spectrum disorder (ASD), do not meet the national physical activity (PA) guidelines. One way to address this problem may be to examine the factors that motivate individuals to engage in PA. However, the majority of current literature does not consider the unique characteristics of individuals with ASD, which may influence their motivation. OBJECTIVE: The purpose of this research was to examine Self-Determination Theory predictors for PA for young adults with ASD. METHODS: Respondents included 143 young adults with ASD who completed a survey pertaining to their motivational process to engage in physical activity, based on self-determination theory variables. RESULTS: Goodness of fit indices reported from a path analysis suggests the current data closely align with the self-determination theory (chi(2) (3, N=143)=11.99, p>.01, GFI=0.97, NFI=0.95, CFI=. 96, RMSEA=0.15). The three basic psychological needs explained 39% of the variance within respondents’ self-determined motivation, and self-determined motivation explained 8% of the variance in PA levels. CONCLUSIONS: These findings support utilizing the self-determination theory within health promotion efforts for young adults with ASD. Practitioners should focus on enhancing the perceived basic psychological needs of young adults within physical activity settings.
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5. Hartmann K, Kozikowski CT, Urbano MR, Williams TV, Ba CL, Peterkin A. {{Autism spectrum disorder in Latin American families: Experiences in Chile}}. {Families, systems & health : the journal of collaborative family healthcare}. 2018; 36(2): 169-74.
INTRODUCTION: The present study provides pilot data investigating relationships between severity of autism spectrum disorder (ASD) traits, community supports, and other family variables as reported by caregivers of children with ASD in Chile. METHOD: An anonymous caregiver survey was developed based on previous ASD survey studies conducted in the United States and direct input from collaborators residing in Chile. Participants included Chilean caregivers of individuals with ASD (N = 50; Mchild age = 6.98). The survey addressed topics regarding the child’s ASD traits, the caregiver’s beliefs and perceptions of ASD, and community supports and engagement. RESULTS: Correlational analyses indicated associations between ASD traits, physician support, family stress, stigma, and community engagement. DISCUSSION: Results from this study highlight the importance of future research to better understand and treat Latin American children with ASD and their families. (PsycINFO Database Record
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6. Heaton P, Tsang WF, Jakubowski K, Mullensiefen D, Allen R. {{Discriminating autism and language impairment and specific language impairment through acuity of musical imagery}}. {Res Dev Disabil}. 2018; 80: 52-63.
Deficits in auditory short-term memory have been widely reported in children with Specific Language Impairment (SLI), and recent evidence suggests that children with Autism Spectrum Disorder and co-morbid language impairment (ALI) experience similar difficulties. Music, like language relies on auditory memory and the aim of the study was to extend work investigating the impact of auditory short-term memory impairments to musical perception in children with neurodevelopmental disorders. Groups of children with SLI and ALI were matched on chronological age (CA), receptive vocabulary, non-verbal intelligence and digit span, and compared with CA matched typically developing (TD) controls, on tests of pitch and temporal acuity within a voluntary musical imagery paradigm. The SLI participants performed at significantly lower levels than the ALI and TD groups on both conditions of the task and their musical imagery and digit span scores were positively correlated. In contrast ALI participants performed as well as TD controls on the tempo condition and better than TD controls on the pitch condition of the task. Whilst auditory short-term memory and receptive vocabulary impairments were similar across ALI and SLI groups, these were not associated with a deficit in voluntary musical imagery performance in the ALI group.
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7. Jacquemont S, Pacini L, Jonch AE, Cencelli G, Rozenberg I, He Y, D’Andrea L, Pedini G, Eldeeb M, Willemsen R, Gasparini F, Tassone F, Hagerman R, Gomez-Mancilla B, Bagni C. {{Protein synthesis levels are increased in a subset of individuals with fragile X syndrome}}. {Hum Mol Genet}. 2018; 27(12): 2039-51.
Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here, we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.
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8. Kim JW, Park K, Kang RJ, Gonzales ELT, Kim DG, Oh HA, Seung H, Ko MJ, Kwon KJ, Kim KC, Lee SH, Chung C, Shin CY. {{Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism}}. {Neuropsychopharmacology}. 2018.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice. We found that Cntnap2 KO mice displayed decreased glutamate receptor expression and transmission. Contrarily, VPA mice exhibited increased glutamate receptor expression and transmission. Next, we investigated whether AMPAR modulators (positive-allosteric-modulator for Cntnap2 KO mice and antagonist for VPA mice) can improve autistic symptoms by normalizing the aberrant excitatory transmission in the respective animal models. Interestingly, the AMPAR modulation specifically ameliorated social deficits in both animal models. These results indicated that AMPAR-derived excitatory neural transmission changes can affect normal social behavior. To validate this, we injected an AMPAR agonist or antagonist in control ICR mice and, interestingly, these treatments impaired only the social behavior, without affecting the repetitive and hyperactive behaviors. Collectively, these results provide insight into the role of AMPARs in the underlying pathophysiological mechanisms of ASD, and demonstrate that modulation of AMPAR can be a potential target for the treatment of social behavior deficits associated with ASD.
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9. Lallar M, Rai A, Srivastava P, Mandal K, Gupta N, Kabra M, Phadke SR. {{Molecular Testing of MECP2 Gene in Rett Syndrome Phenotypes in Indian Girls}}. {Indian pediatrics}. 2018; 55(6): 474-7.
OBJECTIVE: To assess yield of MECP2 gene sequence variations analysis and large deletions in suspected cases of Rett syndrome. DESIGN: Descriptive study. SETTING: Tertiary-care medical genetics center. PATIENTS: Girls with neuroregression, postnatal microcephaly and signs and symptoms suggestive of classical and atypical Rett syndrome were classified into two groups. Group I consisted of girls with Classical and atypical Rett syndrome on basis on the Revised Rett Syndrome diagnostic criteria, 2010. Group II included girls with neuroregression and postnatal microcephaly and other Rett like features but not fulfilling the above criteria. PROCEDURE: Sanger sequencing of coding regions and large deletional analysis of MECP2 gene. OUTCOME MEASURES: Identification of mutation in MECP2 gene. RESULTS: Mutation in MECP2 gene was identified in 74% (14/19) in group I and none (0/17) in group II. The mutation detection rate was 93% (13/14) in group I classical Rett syndrome girls (2 with large deletions identified with Multiplex ligation dependent probe amplification) and 20% (1/5) in group I atypical Rett syndrome girls. One novel MECP2 sequence variation was identified in group I classical Rett syndrome. CONCLUSIONS: The yield of the mutation detection in MECP2 is higher in classical Rett syndrome. In girls with some Rett like features, but not fulfilling revised Rett syndrome diagnostic criteria, mutation testing for MECP2 gene has a low yield.
10. Qian Z, Zhang R, Zhou J, Sun S, Di Y, Ren W, Tian Y. {{RNA-Seq data on prefrontal cortex in valproic acid model of autism and control rats}}. {Data in brief}. 2018; 18: 787-9.
The transcriptome sequencing data of valproic acid (VPA) model of autism and control rats are presented. VPA model of autism was induced by a single intraperitoneal injection of 600mg/kg sodium valproic acid to female rats at day 12.5 post-conception, and the control rats were injected with saline. Male offspring of VPA- or saline-injected dams from different litters were sacrificed on PND 35 (n = three rats/three litters/group). Prefrontal cortex was dissected from both hemispheres, and RNA was isolated. Libraries were prepared and RNA Sequencing (RNA-Seq) was performed following Illumina’s recommendations. Samples are described in the SRA portal (SRP115258) and FASTQ files have been deposited in Sequence Read Archive (accession numbers: SRR5950172 to SRR5950177). The interpretation of these data is presented in the following research article: « Transcriptional and splicing dysregulation in prefrontal cortex of valproic acid induced rat models of autism » (Zhang et al., 2018) [1].
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11. Saxena K, Webster J, Hallas-Potts A, Mackenzie R, Spooner PA, Thomson D, Kind P, Chatterji S, Morris RGM. {{Experiential contributions to social dominance in a rat model of fragile-X syndrome}}. {Proceedings Biological sciences}. 2018; 285(1880).
Social withdrawal is one phenotypic feature of the monogenic neurodevelopmental disorder fragile-X. Using a ‘knockout’ rat model of fragile-X, we examined whether deletion of the Fmr1 gene that causes this condition would affect the ability to form and express a social hierarchy as measured in a tube test. Male fragile-X ‘knockout’ rats living together could successfully form a social dominance hierarchy, but were significantly subordinate to wild-type animals in mixed group cages. Over 10 days of repeated testing, the fragile-X mutant rats gradually showed greater variance and instability of rank during their tube-test encounters. This affected the outcome of future encounters with stranger animals from other cages, with the initial phenotype of wild-type dominance lost to a more complex picture that reflected, regardless of genotype, the prior experience of winning or losing. Our findings offer a novel insight into the complex dynamics of social interactions between laboratory living groups of fragile-X and wild-type rats. Even though this is a monogenic condition, experience has an impact upon future interactions with other animals. Gene/environment interactions should therefore be considered in the development of therapeutics.
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12. Tan DW, Maybery MT, Clarke MW, Di Lorenzo R, Evans MO, Mancinone M, Panos C, Whitehouse AJO. {{No relationship between autistic traits and salivary testosterone concentrations in men from the general population}}. {PLoS One}. 2018; 13(6): e0198779.
It is suggested that testosterone may play a part in the higher prevalence of Autism Spectrum Disorder (ASD) in males compared to females. Previous studies have reported elevated postnatal testosterone levels in children and women with ASD but not in men. We compared levels of salivary testosterone across 67 undergraduate males (Mage 19.5 yrs, SD 1.92) selected for low, mid-range and high levels of autistic traits assessed using the Autism-spectrum Quotient. Analyses revealed no significant differences in testosterone concentrations across the three groups. The current data add to the increasing evidence for the lack of relationship between autistic traits and postnatal levels of testosterone in men.
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13. Tan E, Wu X, Nishida T, Huang D, Chen Z, Yi L. {{Analogical Reasoning in Children With Autism Spectrum Disorder: Evidence From an Eye-Tracking Approach}}. {Front Psychol}. 2018; 9: 847.
The present study examined analogical reasoning in children with autism spectrum disorder (ASD) and its relationship with cognitive and executive functioning and processing strategies. Our findings showed that although children with ASD were less competent in solving analogical problems than typically developing children, this inferior performance was attributable to general cognitive impairments. Eye-movement analyses revealed that children with ASD paid less attention to relational items and showed fewer gaze shifts between relational locations. Nevertheless, these eye-movement patterns did not predict autistic children’s behavioral performance. Together, our findings suggest that ASD per se does not entail impairments in analogical reasoning. The inferior performance of autistic children on analogical reasoning tasks is attributable to deficits in general cognitive and executive functioning.
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14. Torres A, Brownstein CA, Tembulkar SK, Graber K, Genetti C, Kleiman RJ, Sweadner KJ, Mavros C, Liu KX, Smedemark-Margulies N, Maski K, Yang E, Agrawal PB, Shi J, Beggs AH, D’Angelo E, Lincoln SH, Carroll D, Dedeoglu F, Gahl WA, Biggs CM, Swoboda KJ, Berry GT, Gonzalez-Heydrich J. {{De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome}}. {Molecular genetics and metabolism reports}. 2018; 16: 23-9.
Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5 years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient’s father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient’s episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.
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15. Vats P, Juneja M, Mishra D. {{Diagnostic Accuracy of International Epidemiology Network (INCLEN) Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) in Comparison with Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5)}}. {Indian pediatrics}. 2018; 55(6): 482-4.
OBJECTIVE: To compare the diagnostic accuracy of INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) against Diagnostic and Statistical Manual of Mental Disorders – 5 (DSM-5) for the diagnosis of Autism Spectrum Disorder (ASD). METHODS: 118 children aged 2-9 years with symptoms suggestive of ASD were assessed by INDT-ASD and DSM-V by trained personnel. ASD diagnosis by INDT-ASD was compared against the expert’s DSM-5 diagnosis. RESULTS: INDT-ASD had a sensitivity and specificity of 100% and 75%, respectively against DSM-5 for the diagnosis of ASD; specificity for Autistic Disorder was 87%. CONCLUSION: The INDT-ASD has a good sensitivity and specificity against DSM-5, and can continue to be used for the diagnosis of ASD even after the adoption of DSM-5 criteria.
16. Yau CH, Ip CL, Chau YY. {{The therapeutic effect of scalp acupuncture on natal autism and regressive autism}}. {Chinese medicine}. 2018; 13: 30.
Background: Autism spectrum disorders (ASD) is a common disease and the incidence has been rising constantly. Acupuncture is one of the most widely used complementary and alternative medicine therapies. Despite studies had been done on the effectiveness of acupuncture on ASD children, how factors such as chronological age and the onset pattern influence the effectiveness of the therapy remains unclear. The aim of this retrospective study is to know how symptomatology of ASD alters upon the introduction of scalp acupuncture and how do age and onset type affect the effectiveness of the therapy. Methods: ASD children aged 2-11 years old were invited to join the study. In the course of the investigation, they received a total of 30 sessions of scalp acupuncture therapy. They were then evaluated to compare the performance on various aspects before and after the treatment. The influence on the therapeutic effect by factors including chorological age and onset pattern were further taken into consideration and analyzed. In addition, investigation on the relationship between allergies and onset pattern of ASD was performed by statistically analyzing the received epidemiologic data from the participants. Results: 68 children with ASD participated in the study. It is found that the significant effective rate of scalp acupuncture on ASD is 97%. Scalp acupuncture can improve verbal communication problems the most while noise sensitivity improves the least. The therapeutic effectiveness decreases with increasing age and children with natal autism benefit more from acupuncture than those with regressive autism. In the latter part of the study, we observe a positive correlation between the family history of allergy and onset pattern. Conclusion: Scalp acupuncture is an effective treatment for alleviating the symptomatology of ASD. The therapeutic effectiveness is expected to be higher for those patients with natal or early onset of the disorder, and at a younger age when they receive the therapy. The study result helps to formulate an ideal regimen for ASD patients and allow therapists and parents to make appropriate expectation towards the therapeutic outcome of acupuncture. Early intervention of scalp acupuncture therapy recommended. The relationship between the family history of allergic disorder and the onset type of ASD hints that the etiologies of natal and regressive ASD are discrete. It shows a great significance in differentiating the onset pattern in carrying out clinical assessments or researches on ASD patients.Trial registration This retrospective study was approved by the Committee on the Use of Human and Animal Subjects in Teaching and Research, Hong Kong Baptist University on 4th Aug 2017. The retrospectively registered number is HASC/Student/17-18/0115.
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17. Yu L, Zhu X. {{Effectiveness of a SCERTS Model-Based Intervention for Children with Autism Spectrum Disorder (ASD) in Hong Kong: A Pilot Study}}. {J Autism Dev Disord}. 2018.
A SCERTS model-based intervention with different durations (5-month vs. 10-month) was provided to 122 children with autism spectrum disorder (ASD) (age = 53.43 +/- 9.05 months) in Hong Kong. Before and after the intervention, the children were assessed with the Chinese Psychoeducational Profile-Third Edition (CPEP-3) and the Developmental Assessment Chart (DAC). Educators and parents expressed their views toward the intervention in focus groups. Results showed that participating children improved significantly in their social communication and emotional behavior after the intervention, as measured by DAC and CPEP-3. Likewise, educators and parents had positive views toward the intervention and noted the children’s improvement. The results suggest that a SCERTS model-based intervention can improve social communication, emotional regulation, and other skills in children with ASD.
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18. Zerbi V, Ielacqua GD, Markicevic M, Haberl MG, Ellisman MH, A AB, Frick A, Rudin M, Wenderoth N. {{Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories}}. {Cereb Cortex}. 2018; 28(7): 2495-506.
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.
