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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
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PMID:Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. 2560 68

Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors.
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PMID:Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes. 2659 Mar 42

Although autism spectrum disorders (ASDs) share a core set of nosological features, they exhibit substantial genetic heterogeneity. A parsimonious hypothesis posits that dysregulated epigenetic mechanisms represent common pathways in the etiology of ASDs. To investigate this hypothesis, we generated a novel mouse model resulting from brain-specific deletion of chromodomain helicase DNA-binding 5 (Chd5), a chromatin remodeling protein known to regulate neuronal differentiation and a member of a gene family strongly implicated in ASDs. RNA sequencing of Chd5-/- mouse forebrain tissue revealed a preponderance of changes in expression of genes important in cellular development and signaling, sociocommunicative behavior and ASDs. Pyramidal neurons cultured from Chd5-/- cortex displayed alterations in dendritic morphology. Paralleling ASD nosology, Chd5-/- mice exhibited abnormal sociocommunicative behavior and a strong preference for familiarity. Chd5-/- mice further showed deficits in responding to the distress of a conspecific, a mouse homolog of empathy. Thus, dysregulated chromatin remodeling produces a pattern of transcriptional, neuronal and behavioral effects consistent with the presentation of ASDs.
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PMID:Mice lacking the chromodomain helicase DNA-binding 5 chromatin remodeler display autism-like characteristics. 2860 55

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that has a strong genetic component. Disruptions of FOXP1, a transcription factor expressed in the developing cerebral cortex, were associated with ASD. FOXP1(R525X) is a de novo heterozygous mutation found in patients with autism and severe mental retardation. To explore the neuronal basis of FOXP1(R525X) in ASD, we created Foxp1(R521X), a mouse homolog of the human variant. Ectopic expression of Foxp1(R521X) led to cytoplasmic aggregates and activated macroautophagy in neuroblastoma N2a cells and the developing neuronal cells. Cortical neurons expressing Foxp1(R521X) exhibited delayed migration and altered dendritic morphology. As a control, mutant Y435X that was expressed diffusively in the cytoplasm did not induce autophagy and migration delay in the cortex. The embryonic cortical cells had a minimal activity of nonsense-mediated mRNA decay (NMD) as assayed by a splicing-dependent NMD reporter. We hypothesize that the developing neuronal cells use autophagy but not NMD as a safeguard mechanism against nonsense mutant aggregates, resulting in impairment of the cortical development. This study suggests a novel mechanism other than heterozygous loss of FOXP1 for the development of ASD and may advance our understanding of the complex relationships between gene mutation and the related psychiatric disorders.
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PMID:An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons. 3012 90

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.
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PMID:Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice. 3065 3