RESUMEN
Immunoglobulin G (IgG) autoantibodies reactive to fetal brain proteins in mothers of children with ASD have been described by several groups. To understand their pathologic significance, we developed a mouse model of maternal autoantibody related ASD (MAR-ASD) utilizing the peptide epitopes from human autoantibody reactivity patterns. Male and female offspring prenatally exposed to the salient maternal autoantibodies displayed robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults. In the present study, neuroanatomical differences in adult MAR-ASD and control offspring were assessed via high-resolution ex vivo magnetic resonance imaging (MRI) at 6 months of age. Of interest, MAR-ASD mice displayed significantly larger total brain volume and of the 159 regions examined, 31 were found to differ significantly in absolute volume (mm3) at an FDR of <5%. Specifically, the absolute volumes of several white matter tracts, cortical regions, and basal nuclei structures were significantly increased in MAR-ASD animals. These phenomena were largely driven by female MAR-ASD offspring, as no significant differences were seen with either absolute or relative regional volume in male MAR-ASD mice. However, structural covariance analysis suggests network-level desynchronization in brain volume in both male and female MAR-ASD mice. Additionally, preliminary correlational analysis with behavioral data relates that volumetric increases in numerous brain regions of MAR-ASD mice were correlated with social interaction and repetitive self-grooming behaviors in a sex-specific manner. These results demonstrate significant sex-specific effects in brain size, regional relationships, and behavior for offspring prenatally exposed to MAR-ASD autoantibodies relative to controls.
Asunto(s)
Trastorno del Espectro Autista , Animales , Trastorno del Espectro Autista/metabolismo , Autoanticuerpos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Epítopos/metabolismo , Femenino , Masculino , RatonesRESUMEN
Immune dysregulation has been noted consistently in individuals with autism spectrum disorder (ASD) and their families, including the presence of autoantibodies reactive to fetal brain proteins in nearly a quarter of mothers of children with ASD versus <1% in mothers of typically developing children. Our lab recently identified the peptide epitope sequences on seven antigenic proteins targeted by these maternal autoantibodies. Through immunization with these peptide epitopes, we have successfully created an endogenous, antigen-driven mouse model that ensures a constant exposure to the salient autoantibodies throughout gestation in C57BL/6J mice. This exposure more naturally mimics what is observed in mothers of children with ASD. Male and female offspring were tested using a comprehensive sequence of behavioral assays, as well as measures of health and development highly relevant to ASD. We found that MAR-ASD male and female offspring had significant alterations in development and social interactions during dyadic play. Although 3-chambered social approach was not significantly different, fewer social interactions with an estrous female were noted in the adult male MAR-ASD animals, as well as reduced vocalizations emitted in response to social cues with robust repetitive self-grooming behaviors relative to saline treated controls. The generation of MAR-ASD-specific epitope autoantibodies in female mice prior to breeding created a model that demonstrates for the first time that ASD-specific antigen-induced maternal autoantibodies produced alterations in a constellation of ASD-relevant behaviors.
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Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/fisiopatología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Epítopos/inmunología , Animales , Trastorno del Espectro Autista/psicología , Trastorno Autístico/inmunología , Trastorno Autístico/fisiopatología , Trastorno Autístico/psicología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BLRESUMEN
Angelman syndrome is a rare neurodevelopmental disorder caused by a mutation in the maternal allele of the gene Ube3a The primary symptoms of Angelman syndrome are severe cognitive deficits, impaired motor functions, and speech disabilities. Analogous phenotypes have been detected in young adult Ube3a mice. Here, we investigate cognitive phenotypes of Ube3a mice as compared to wild-type littermate controls at an older adult age. Water maze spatial learning, swim speed, and rotarod motor coordination and balance were impaired at 6 mo of age, as predicted. Based on previous findings of reduced brain-derived neurotrophic factor in Ube3a mice, a novel therapeutic target, the TrkB agonist 7,8-DHF, was interrogated. Semichronic daily treatment with 7,8-DHF, 5 mg/kg i.p., did not significantly improve the impairments in performance during the acquisition of the water maze hidden platform location in Ube3a mice, after training with either massed or spaced trials, and had no effect on the swim speed and rotarod deficits. Robust behavioral phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Our results suggest that motor deficits could offer useful outcome measures for preclinical testing of many pharmacological targets, with the goal of reducing symptoms in adults with Angelman syndrome.
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Síndrome de Angelman/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Flavonas/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Glicoproteínas de Membrana/agonistas , Actividad Motora/efectos de los fármacos , Factores de Edad , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Noqueados , Fenotipo , Proteínas Tirosina Quinasas , Ubiquitina-Proteína LigasasRESUMEN
Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.
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Proteína 2 de Unión a Metil-CpG/genética , Actividad Motora/genética , Síndrome de Rett/genética , Animales , Modelos Animales de Enfermedad , Exones/genética , Femenino , Regulación de la Expresión Génica/genética , Heterocigoto , Humanos , Masculino , Ratones , Actividad Motora/fisiología , Mutación , Fenotipo , Isoformas de Proteínas/genética , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatologíaRESUMEN
The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Relacionadas con la Autofagia/genética , Encéfalo/embriología , Encéfalo/patología , Variación Genética/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Proteínas Adaptadoras Transductoras de Señales/química , Adolescente , Animales , Proteínas Relacionadas con la Autofagia/química , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Tamaño de los Órganos , Estructura Secundaria de ProteínaRESUMEN
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams. Given that RTT patients are predominantly female, we conducted a systematic analysis of developmental milestones, sensory abilities, and motor deficits, following the longitudinal decline of function from early postnatal to adult ages in female Mecp2 heterozygotes of the conventional Bird line (Mecp2tm1.1bird-/+), as compared to their female wildtype littermate controls. Further, we assessed the impact of postnatal maternal environment on developmental milestones and behavioral phenotypes. Cross-fostering to CD1 dams accelerated several developmental milestones independent of genotype, and induced earlier onset of weight gain in adult female Mecp2tm1.1bird-/+ mice. Cross-fostering improved the sensitivity of a number of motor behaviors that resulted in observable deficits in Mecp2tm1.1bird-/+ mice at much earlier (6-7 weeks) ages than were previously reported (6-9 months). Our findings indicate that female Mecp2tm1.1bird-/+ mice recapitulate many of the motor aspects of RTT syndrome earlier than previously appreciated. In addition, rearing conditions may impact the phenotypic severity and improve the ability to detect genotype differences in female Mecp2 mutant mice.
Asunto(s)
Síndrome de Rett/diagnóstico , Animales , Conducta Animal , Modelos Animales de Enfermedad , Ambiente , Femenino , Estudios de Asociación Genética , Genotipo , Heterocigoto , Masculino , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Ratones Noqueados , Destreza Motora/fisiología , Fenotipo , Síndrome de Rett/genética , Síndrome de Rett/veterinariaRESUMEN
Autism is a neurodevelopmental disorder, diagnosed behaviorally by social and communication deficits, repetitive behaviors, and restricted interests. Recent genome-wide exome sequencing has revealed extensive overlap in risk genes for autism and for cancer. Understanding the genetic commonalities of autism(s) and cancer(s), with a focus on mechanistic pathways, could lead to repurposed therapeutics.
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Trastorno Autístico/genética , Predisposición Genética a la Enfermedad , Neoplasias/genética , HumanosRESUMEN
Intellectual and developmental disabilities (IDDs) are a common group of disorders that frequently share overlapping symptoms, including cognitive deficits, altered attention, seizures, impaired social interactions, and anxiety. The causes of these disorders are varied ranging from early prenatal/postnatal insults to genetic variants that either cause or are associated with an increased likelihood of an IDD. As many of the symptoms observed in individuals with IDDs are a manifestation of altered nervous system function resulting in altered behaviors, it should not be surprising that the field is very dependent upon in vivo model systems. This special issue of Neurobiology of Learning and Memory is focused on the methods and approaches that are being used to model and understand these disorders in mammals. While surveys by the Pew Foundation continue to find a high degree of confidence/trust in scientists by the public, several recent studies have documented issues with reproducibility in scientific publications. This special issue includes both primary research articles and review articles in which careful attention has been made to transparently report methods and use rigorous approaches to ensure reproducibility. Although there have been and will continue to be remarkable advances for treatment of subset of IDDs, it is clear that this field is still in its early stages. There is no doubt that the strategies being used to model IDDs will continue to evolve. We hope this special issue will support this evolution so that we can maintain the trust of the public and elected officials, and continue developing evidence-based approaches to new therapeutics.
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Discapacidades del Desarrollo/psicología , Modelos Animales de Enfermedad , Discapacidad Intelectual/psicología , Animales , Discapacidades del Desarrollo/etiología , Humanos , Discapacidad Intelectual/etiologíaRESUMEN
Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.
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Investigación Conductal/métodos , Ratones/psicología , Ratas/psicología , Animales , Investigación Conductal/normas , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.
Asunto(s)
Trastorno Autístico/fisiopatología , Cerebelo/fisiopatología , Células de Purkinje/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Animales , Trastorno Autístico/complicaciones , Trastorno Autístico/genética , Trastorno Autístico/patología , Conducta Animal/efectos de los fármacos , Recuento de Células , Forma de la Célula/efectos de los fármacos , Cerebelo/efectos de los fármacos , Cerebelo/patología , Aseo Animal/efectos de los fármacos , Aseo Animal/fisiología , Heterocigoto , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mutación/genética , Células de Purkinje/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Sirolimus/farmacología , Sinapsis/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia , Vocalización Animal/efectos de los fármacos , Vocalización Animal/fisiologíaRESUMEN
Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2-knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced â¼35% in forebrain, they were increased 40 -: 75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5 -: 15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of ß-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.
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Neuronas Dopaminérgicas/metabolismo , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/genética , Neurogénesis , Prosencéfalo/metabolismo , Neuronas Serotoninérgicas/metabolismo , Animales , Neuronas Dopaminérgicas/fisiología , Proteína Doblecortina , Femenino , Eliminación de Gen , Humanos , Masculino , Ratones , Ratones Noqueados , Norepinefrina/metabolismo , Prosencéfalo/crecimiento & desarrollo , Prosencéfalo/patología , Prosencéfalo/fisiopatología , Neuronas Serotoninérgicas/fisiología , NataciónRESUMEN
Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/-) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/- mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/-, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/- mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey-Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/- mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/- failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/-. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/- mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome.
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Trastorno Autístico/complicaciones , Trastorno Autístico/psicología , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/psicología , Trastornos del Conocimiento/etiología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/psicología , Aprendizaje , Reconocimiento en Psicología , Animales , Trastorno Autístico/fisiopatología , Deleción Cromosómica , Trastornos de los Cromosomas/fisiopatología , Cromosomas Humanos Par 16 , Trastornos del Conocimiento/genética , Condicionamiento Psicológico , Señales (Psicología) , Discriminación en Psicología , Miedo , Femenino , Heterocigoto , Discapacidad Intelectual/fisiopatología , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/genética , Masculino , Ratones Transgénicos , Pruebas Psicológicas , Aprendizaje Inverso , Percepción Social , Memoria Espacial , Natación , Percepción VisualRESUMEN
Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of autism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
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Trastorno Autístico/genética , Trastorno Autístico/psicología , Modelos Animales de Enfermedad , Relaciones Interpersonales , Fenotipo , Animales , Trastorno Autístico/terapia , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/psicología , Humanos , Ratones , Mutación/genética , Trastorno de la Conducta Social/genética , Trastorno de la Conducta Social/psicología , Trastorno de la Conducta Social/terapiaRESUMEN
Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
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Trastorno Autístico/genética , Receptores de Serotonina/fisiología , Serotonina/sangre , Conducta Social , Conducta Estereotipada , Animales , Trastorno Autístico/sangre , Trastorno Autístico/fisiopatología , Modelos Animales de Enfermedad , Homeostasis , RatonesRESUMEN
Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.
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Trastorno Autístico/genética , Proteínas Portadoras/genética , Potenciales Postsinápticos Excitadores/genética , Mutación/genética , Inhibición Neural/genética , Fenotipo , Transmisión Sináptica/genética , Factores de Edad , Animales , Trastorno Autístico/psicología , Femenino , Tamización de Portadores Genéticos , Ácido Glutámico/genética , Homocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido NerviosoRESUMEN
Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Autism-relevant phenotypes in the inbred mouse strain BTBR T+tf/J (BTBR) offer translational tools to discover biological mechanisms underlying unusual mouse behaviors analogous to symptoms of autism. Two of the most consistent findings with BTBR are lack of sociability as measured by the three-chamber social approach task and increased amount of time engaged in self-grooming in an empty cage. Here we evaluated BTBR as compared to two typical inbred strains with high sociability and low self-grooming, C57BL/6J (B6) and FVB/AntJ (FVB), on both the automated three-chambered social approach task and repetitive self-grooming assays. Brains from the behaviorally tested mice were analyzed using magnetic resonance imaging and diffusion tensor imaging to investigate potential neuroanatomical abnormalities throughout the brain; specifically, to discover neuroanatomical mechanisms which could explain the autism-relevant behavioral abnormalities. Significant differences in volume and white matter microstructure were detected in multiple anatomical regions throughout the brain of BTBR compared to B6 and FVB. Further, significant correlations were found between behavioral measures and areas of the brain known to be associated with those behaviors. For example, striatal volume was strongly correlated to time spent in self-grooming across strains. Our findings suggest that neuropathology exists in BTBR beyond the previously reported white matter abnormalities in the corpus callosum and hippocampal commissure and that these brain differences may be related to the behavioral abnormalities seen in BTBR.
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Trastorno Autístico/patología , Encéfalo/patología , Imagen de Difusión Tensora , Imagen por Resonancia Magnética , Animales , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones EndogámicosRESUMEN
More than 100 single gene mutations and copy number variants convey risk for autism spectrum disorder. To understand the extent to which each mutation contributes to the trajectory of individual symptoms of autism, molecular genetics laboratories have introduced analogous mutations into the genomes of laboratory mice and other species. Over the past twenty years, behavioral neuroscientists discovered the consequences of mutations in many risk genes for autism in animal models, using assays with face validity to the diagnostic and associated behavioral symptoms of people with autism. Identified behavioral phenotypes complement electrophysiological, neuroanatomical, and biochemical outcome measures in mutant mouse models of autism. This review describes the history of phenotyping assays in genetic mouse models, to evaluate social and repetitive behaviors relevant to the primary diagnostic criteria for autism. Robust phenotypes are currently employed in translational investigations to discover effective therapeutic interventions, representing the future direction of an intensely challenging research field.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Animales , Trastorno Autístico/genética , Trastorno del Espectro Autista/genética , Conducta Animal/fisiología , Fenotipo , Modelos Animales de EnfermedadRESUMEN
A microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA-approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine-learning approach to analyze behavior, one lab found that arbaclofen also rescued differences in exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.
RESUMEN
BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders.
Asunto(s)
Ansiedad/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos de la Memoria/metabolismo , Memoria a Corto Plazo/fisiología , Convulsiones/genética , Estimulación Acústica , Análisis de Varianza , Animales , Ansiedad/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Adaptación a la Oscuridad/genética , Modelos Animales de Enfermedad , Electrochoque/efectos adversos , Ensayo de Inmunoadsorción Enzimática/métodos , Conducta Exploratoria/fisiología , Miedo/psicología , Femenino , Suspensión Trasera/métodos , Humanos , Inhibición Psicológica , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Dimensión del Dolor , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/fisiopatología , Conducta Social , Natación/psicologíaRESUMEN
The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) contribute to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Here, we characterized the phenotype of oxytocin receptor (OTR) and vasopressin-1A receptor (V1AR) null mutant mice in a battery of pain assays. Surprisingly, OTR knock-out mice displayed a pain phenotype identical to their wild-type littermates. Moreover, systemic administration of OXT dose-dependently produced analgesia in both wild-type and OTR knock-out mice in three different assays, the radiant-heat paw withdrawal test, the von Frey test of mechanical sensitivity, and the formalin test of inflammatory nociception. In contrast, OXT-induced analgesia was completely absent in V1AR knock-out mice. In wild-type mice, OXT-induced analgesia could be fully prevented by pretreatment with a V1AR but not an OTR antagonist. Receptor binding studies demonstrated that the distribution of OXT and AVP binding sites in mouse lumbar spinal cord resembles the pattern observed in rat. AVP binding sites diffusely label the lumbar spinal cord, whereas OXT binding sites cluster in the substantia gelatinosa of the dorsal horn. In contrast, quantitative real-time reverse transcription (RT)-PCR revealed that V1AR but not OTR mRNA is abundantly expressed in mouse dorsal root ganglia, where it localizes to small- and medium-diameter cells as shown by single-cell RT-PCR. Hence, V1ARs expressed in dorsal root ganglia might represent a previously unrecognized target for the analgesic action of OXT and AVP.