Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
Animals ; Dentate Gyrus/metabolism* ; Mice ; Morphogenesis/physiology* ; Neurons/pathology* ; Cell Movement ; Mice, Inbred C57BL ; Autism Spectrum Disorder/pathology* ; Mice, Knockout ; Neural Stem Cells ; Male ; Neurogenesis ; Autistic Disorder/genetics*

The cerebellum is heavily connected with other brain regions, sub-serving not only motor but also nonmotor functions. Genetic mutations leading to cerebellar dysfunction are associated with mental diseases, but cerebellar outputs have not been systematically studied in this context. Here, we present three dimensional distributions of 50,168 target neurons of cerebellar nuclei (CN) from wild-type mice and Nlgn3R451C mutant mice, a mouse model for autism. Our results derived from 36 target nuclei show that the projections from CN to thalamus, midbrain and brainstem are differentially affected by Nlgn3R451C mutation. Importantly, Nlgn3R451C mutation altered the innervation power of CN→zona incerta (ZI) pathway, and chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social defects in Nlgn3R451C mice. Our study highlights potential role of cerebellar outputs in the pathogenesis of autism and provides potential new therapeutic strategy for this disease.
Animals ; Mice ; Disease Models, Animal ; Cerebellar Nuclei ; Autistic Disorder/pathology* ; Neurons/metabolism* ; Mutation ; Nerve Tissue Proteins/metabolism* ; Male ; Membrane Proteins ; Cell Adhesion Molecules, Neuronal

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.
Adult ; Animals ; Autistic Disorder ; Blood-Brain Barrier ; Cell Death ; Cerebrospinal Fluid ; Grooming ; Humans ; Injections, Intraperitoneal ; Mass Screening ; Mice ; Mice, Inbred ICR ; N-Methylaspartate ; Neurons ; Nociception ; Pathology ; Synaptic Transmission ; Tail

Autism spectrum disorder (ASD) is characterized by persistent deficits within two core symptom domains: social communication and restricted, repetitive behaviors. Although numerous studies have reported psychopharmacological treatment outcomes for the core symptom domains of ASD, there are not enough studies on fundamental treatments based on the etiological pathology of ASD. Studies on candidate medications related to the pathogenesis of ASD, such as naltrexone and secretin, were conducted, but the results were inconclusive. Oxytocin has been identified as having an important role in maternal behavior and attachment, and it has been recognized as a key factor in the social developmental deficit seen in ASD. Genetic studies have also identified associations between ASD and the oxytocin pathway. As ASD has its onset in infancy, parents are willing to try even experimental or unapproved treatments in an effort to avoid missing the critical period for diagnosis and treatment, which can place their child in an irreversible state. While therapeutic application of oxytocin for ASD is in its early stages, we have concluded that oxytocin would be a promising therapeutic substance via a thorough literature review focusing on the following: the relationship between oxytocin and sociality; single nucleotide polymorphisms as a biological marker of ASD; and validity verification of oxytocin treatment in humans. We also reviewed materials related to the mechanism of oxytocin action that may support its potential application in treating ASD.
Autistic Disorder* ; Child ; Autism Spectrum Disorder* ; Critical Period (Psychology) ; Diagnosis ; Humans ; Maternal Behavior ; Naltrexone ; Oxytocin* ; Parents ; Pathology ; Polymorphism, Single Nucleotide ; Secretin ; Social Change ; Biomarkers

PURPOSE: The study was done to identify the construct validity and reliability of the life transition scale (LTS) for parents who have children with autism. METHODS: Exploratory factor analysis (EFA) and confirmative factor analysis (CFA) were conducted to identify the most adequate measurement model for structural validity. Convergent validity and discriminant validity were also conducted for structural validity. Data were collected from 208 parents through self-reported questionnaires and analyzed with SPSS/WIN 15.0 and AMOS 20.0 version. RESULTS: A four factor-structure was validated (chi2=541.23, p<.001, GFI=.82, RMSEA=.07, IFI=.89, CFI=.89, PNFI=.73, Q (chi2/df)=2.20) at the 3rd order of EFA and CFA, and factors were named as denying, wandering, despairing, and accepting. Both convergent and determinant validity for LTS were 100%. Cronbach's alphas for the reliability of each structure were .77-.90 and .83 for total structure. CONCLUSION: The four structures, 24-item instrument showed satisfactory reliability and validity. LTS has the potential to be appropriate for assessing the transition process of life for parents who have children with autism and provides basic directions for differentiated support and care at each stage.
Adaptation, Physiological ; Adult ; Autistic Disorder/diagnosis/*pathology ; Child ; Child, Preschool ; Factor Analysis, Statistical ; Female ; Humans ; Male ; Middle Aged ; Parents/*psychology ; Quality of Life ; Questionnaires ; Severity of Illness Index

OBJECTIVETo explore the effectiveness of electro-acupuncture (EA) in the treatment of childhood autism (CA) and evaluate its effectiveness using single photon emission computed tomography (SPECT).

METHODSA total of 55 CA patients (4.52±2.73 years) were enrolled in this study. All patients received EA treatments and were examined by SPECT before and after treatments.

RESULTSFollowing treatment, the intracerebral multiple focal radioactivity distribution defect areas of CA patients were observed to be partially filled. Specifically, significant differences in the ratios of regional cerebral blood flow and global cerebral blood flow before (Fb) and after (Fe) EA treatment in different lesions were observed (in the left prefrontal cortex, t=5.01, P<0.01; in the right prefrontal cortex, t=2.32, P<0.05; in the left temporal lobe, t=4.54, P<0.01; in the right temporal lobe, t=2.90, P<0.05; in the left Broca's area, t=5.82, P<0.01). After EA treatment, the patients exhibited symptomatic relief.

CONCLUSIONEA is useful to treat CA and SPECT can be used to evaluate the effectiveness of this treatment.

Autistic Disorder ; diagnostic imaging ; physiopathology ; therapy ; Brain ; blood supply ; diagnostic imaging ; pathology ; physiopathology ; Cerebrovascular Circulation ; Child ; Electroacupuncture ; Humans ; Imaging, Three-Dimensional ; Tomography, Emission-Computed, Single-Photon ; methods ; Treatment Outcome

PURPOSE: The purpose of this research was to develop a scale to measure the life transition process of parents of children with autism, against the backdrop of a lack of research on this topic. METHODS: Seventy preliminary items were drawn from previous qualitative research, and content validity was tested by three professors as well as three parents of children with autism. A questionnaire survey was also done between August 2011 and February 2012. Data were collected from 207 parents of children with autism and analyzed using descriptive statistics, item analysis, Cronbach's alpha, Pearson correlation coefficients, and factor analysis with the SPSS Win 15.0 program. RESULTS: Twenty-nine items were selected to constitute the appropriate measuring scale and categorized into 5 factors explaining 63.2% of the total variance. The 5 factors were named; stages of denial (5 items), wandering (6 items), devotion (7 items), frustration (3 items), and finally acceptance (8 items). Cronbach's alpha for the 29 items was .80. CONCLUSION: The results of this study not only suggest assessment criteria for the life transition process of parents who have children with autism but also provide basic directions for program development to provide differentiated support and care at each stage.
*Adaptation, Psychological ; Adolescent ; Adult ; Autistic Disorder/*pathology ; Child ; Child, Preschool ; Depression/pathology ; Fathers/*psychology ; Female ; Humans ; Male ; Middle Aged ; Mothers/*psychology ; *Program Development ; Qualitative Research ; Questionnaires ; Young Adult

PURPOSE: Fragile X syndrome is an X-llinked genetic disorder and is characterized by mental retardation, learning disability, behavior disorder, and autism with typical elongated face, large ears, and macro-orchidism. Recent reports have focused attention on the EEG finding of this syndrome, which is a particular paroxysmal pattern during sleep (mono or diphasic centrotemporal spikes) and awake state (background slowing). In this study, we analyzed the clinical characteristics of fragile X syndrome patients and observed whether a particular EEG pattern is associated with this syndrome or not. METHODS: 7 cases of fragile X syndrome, diagnosed at Sowha Children's Hospital and Cha General Hospital from August 1993 to February 1995, were analyzed retrospectively in terms of typical phenotypes and clinical & EEG characteristics. The patients were diagnosed by Southern blotting and polymerase chain reaction (PCR) method. RESULTS: 1) The subjects were all male and the mean age was 5.8 years old (2Y-11Y). 2) Typical phenotype of long elongated face, macro-orchidism, large ears, and large head are noted in 2/3 of the subject. 3) Developmental delay, mental retardation, learning disability, attention deficit, hyperactivity, and autism are noted in 2/3 of the subject. 4) Seizure is noted in one case and EEG was performed in 6 cases, regardless of the presence of seizures. Abnormal findings including centrotemporal sharps and background slowing are noted in one case, each. 5) By molecular diagnostic methods including Southern blotting and PCR, 3 cases of affected male and 4 of normal transmitting male were diagnosed. CONCLUSIONS: 1) The typical phenotype of fragile X syndrome is long elongated face, macro-orchidism, large ears and large head. 2) The non-physical characteristics of fragile X syndrome are developmental delay, mental retardation, learning disability, attention deficit, hyperactivity, and autism. 3) The characteristic EEG findings of fragile X syndrome known by literature are noted in 2 among 6 cases, which means the specificity is high even though the sensitivity is low. This allows us to propose this EEG pattern as an important "marker" in the diagnosis of fragile X syndrome. However, the number of the subject is too small to conclude now. Further accumulation of cases is reguired.
Autistic Disorder ; Blotting, Southern ; Diagnosis ; Ear ; Electroencephalography* ; Fragile X Syndrome* ; Head ; Hospitals, General ; Humans ; Intellectual Disability ; Learning Disorders ; Male ; Pathology, Molecular ; Phenotype ; Polymerase Chain Reaction ; Retrospective Studies ; Seizures ; Sensitivity and Specificity