RESUMEN
Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene (Ube3a) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1 to 2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We show that mice with extra copies of Ube3a exhibit sex-biasing effects on brain connectomics and autism-relevant behaviors. These effects are associated with transcriptional dysregulation of autism-associated genes, as well as genes differentially expressed in 15q duplication and in autistic people. Increased Ube3a dosage also affects expression of genes on the X chromosome, genes influenced by sex steroid hormone, and genes sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sex-differential mechanisms.
Asunto(s)
Trastorno Autístico , Transcriptoma , Ubiquitina-Proteína Ligasas , Animales , Masculino , Femenino , Trastorno Autístico/genética , Ratones , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Humanos , Conducta Animal , Caracteres Sexuales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Predisposición Genética a la EnfermedadRESUMEN
GABAergic interneurons and perineuronal nets (PNNs) are important regulators of plasticity throughout life and their dysfunction has been implicated in the pathogenesis of several neuropsychiatric conditions, including autism spectrum disorders (ASD). PNNs are condensed portions of the extracellular matrix (ECM) that are crucial for neural development and proper formation of synaptic connections. We previously showed a reduced expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of adult mice lacking the Engrailed2 gene (En2-/- mice), a mouse model of ASD. Since alterations in PNNs have been proposed as a possible pathogenic mechanism in ASD, we hypothesized that the PNN dysfunction may contribute to the neural and behavioral abnormalities of En2-/- mice. Here, we show an increase in the PNN fluorescence intensity, evaluated by Wisteria floribunda agglutinin, in brain regions involved in social behavior and somatosensory processing. In addition, we found that En2-/- mice exhibit altered texture discrimination through whiskers and display a marked decrease in the preference for social novelty. Our results raise the possibility that altered expression of PNNs, together with defects of GABAergic interneurons, might contribute to the pathogenesis of social and sensory behavioral abnormalities.
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Proteínas de Homeodominio , Ratones Noqueados , Proteínas del Tejido Nervioso , Lectinas de Plantas , Conducta Social , Vibrisas , Animales , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Masculino , Ratones Endogámicos C57BL , Matriz Extracelular/metabolismo , Interneuronas/metabolismo , Modelos Animales de Enfermedad , Ratones , Corteza Somatosensorial/metabolismo , Discriminación en Psicología/fisiología , Receptores N-Acetilglucosamina/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
Ataxia-Telangiectasia Mutated (ATM) is a serine/threonine protein kinase principally known to orchestrate DNA repair processes upon DNA double-strand breaks (DSBs). Mutations in the Atm gene lead to Ataxia-Telangiectasia (AT), a recessive disorder characterized by ataxic movements consequent to cerebellar atrophy or dysfunction, along with immune alterations, genomic instability, and predisposition to cancer. AT patients show variable phenotypes ranging from neurologic abnormalities and cognitive impairments to more recently described neuropsychiatric features pointing to symptoms hardly ascribable to the canonical functions of ATM in DNA damage response (DDR). Indeed, evidence suggests that cognitive abilities rely on the proper functioning of DSB machinery and specific synaptic changes in central neurons of ATM-deficient mice unveiled unexpected roles of ATM at the synapse. Thus, in the present review, upon a brief recall of DNA damage responses, we focus our attention on the role of ATM in neuronal physiology and pathology and we discuss recent findings showing structural and functional changes in hippocampal and cortical synapses of AT mouse models. Collectively, a deeper knowledge of ATM-dependent mechanisms in neurons is necessary not only for a better comprehension of AT neurological phenotypes, but also for a higher understanding of the pathological mechanisms in neurodevelopmental and degenerative disorders involving ATM dysfunctions.
Asunto(s)
Ataxia Telangiectasia , Enfermedades Neurodegenerativas , Animales , Ratones , Ataxia Telangiectasia/genética , Reparación del ADN , Interneuronas , Neuronas , HumanosRESUMEN
Interest in the function of ataxia-telangiectasia-mutated protein (ATM) is extensively growing as evidenced by preclinical studies that continuously link ATM with new intracellular pathways. Here, we exploited Atm+/- and Atm-/- mice and demonstrate that cognitive defects are rescued by the delivery of the antidepressant Fluoxetine (Fluox). Fluox increases levels of the chloride intruder NKCC1 exclusively at hippocampal level suggesting an ATM context-specificity. A deeper investigation of synaptic composition unveils increased Gluk-1 and Gluk-5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not in the cortex, of Atm+/- and Atm-/- mice. Analysis of postsynaptic fractions and confocal studies indicates that KARs are presynaptic while in vitro and ex vivo electrophysiology that are fully active. These changes are (i) linked to KCC2 activity, as the KCC2 blockade in Atm+/- developing neurons results in reduced KARs levels and (ii) developmental regulated. Indeed, the pharmacological inhibition of ATM kinase in adults produces different changes as identified by RNA-seq investigation. Our data display how ATM affects both inhibitory and excitatory neurotransmission, extending its role to a variety of neurological and psychiatric disorders.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Hipocampo , Simportadores , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Hipocampo/metabolismo , Humanos , Ratones , Neuronas/metabolismo , Receptores de Ácido Kaínico , Simportadores/genética , Simportadores/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
Sensory abnormalities are a common feature in autism spectrum disorders (ASDs). Tactile responsiveness is altered in autistic individuals, with hypo-responsiveness being associated with the severity of ASD core symptoms. Similarly, sensory abnormalities have been described in mice lacking ASD-associated genes. Loss-of-function mutations in CNTNAP2 result in cortical dysplasia-focal epilepsy syndrome (CDFE) and autism. Likewise, Cntnap2-/- mice show epilepsy and deficits relevant with core symptoms of human ASDs, and are considered a reliable model to study ASDs. Altered synaptic transmission and synchronicity found in the cerebral cortex of Cntnap2-/- mice would suggest a network dysfunction. Here, we investigated the neural substrates of whisker-dependent responses in Cntnap2+/+ and Cntnap2-/- adult mice. When compared to controls, Cntnap2-/- mice showed focal hyper-connectivity within the primary somatosensory cortex (S1), in the absence of altered connectivity between S1 and other somatosensory areas. This data suggests the presence of impaired somatosensory processing in these mutants. Accordingly, Cntnap2-/- mice displayed impaired whisker-dependent discrimination in the textured novel object recognition test (tNORT) and increased c-fos mRNA induction within S1 following whisker stimulation. S1 functional hyperconnectivity might underlie the aberrant whisker-dependent responses observed in Cntnap2-/- mice, indicating that Cntnap2 mice are a reliable model to investigate sensory abnormalities that characterize ASDs.
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Trastorno del Espectro Autista , Trastorno Autístico , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Animales , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Corteza Cerebral , Proteínas de la Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Corteza Somatosensorial , VibrisasRESUMEN
Immune system dysfunction has been described in autism spectrum disorder. Here we tested the hypothesis that cerebellar defects are accompanied by immune dysfunction in adult mice lacking the autism-candidate gene Engrailed 2 (En2). Gene ontology analyses revealed that biological processes related to immune function were over-represented in the cerebellar transcriptome of En2-/- mice. Pro-inflammatory molecules and chemokines were reduced in the En2-/- cerebellum compared to controls. Conversely, pro-inflammatory molecules were increased in the peripheral blood of mutant mice. Our results suggest a link between immune dysfunction and cerebellar defects detected in En2-/- mice.
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Trastorno del Espectro Autista , Trastorno Autístico , Proteínas de Homeodominio , Proteínas del Tejido Nervioso , Animales , Trastorno Autístico/genética , Cerebelo/inmunología , Cerebelo/fisiopatología , Proteínas de Homeodominio/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genéticaRESUMEN
Abnormal tactile response is an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to tactile stimuli is often associated with the severity of ASDs core symptoms. Patients with Phelan-McDermid syndrome (PMS), caused by mutations in the SHANK3 gene, show ASD-like symptoms associated with aberrant tactile responses. The neural underpinnings of these abnormalities are still poorly understood. Here we investigated, in Shank3b-/- adult mice, the neural substrates of whisker-guided behaviors, a key component of rodents' interaction with the surrounding environment. We assessed whisker-dependent behaviors in Shank3b-/- adult mice and age-matched controls, using the textured novel object recognition (tNORT) and whisker nuisance (WN) test. Shank3b-/- mice showed deficits in whisker-dependent texture discrimination in tNORT and behavioral hypo-responsiveness to repetitive whisker stimulation in WN. Sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA induction, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutants, in the absence of altered connectivity between S1 and other somatosensory areas. Impaired crosstalk between hippocampus and S1 might underlie Shank3b-/- hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable somatosensory dysfunction in ASD.
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Trastornos de los Cromosomas , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso , Vibrisas , Animales , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas del Tejido Nervioso/genética , Corteza Somatosensorial/metabolismo , Vibrisas/fisiologíaRESUMEN
Foxg1 is an ancient transcription factor gene orchestrating a number of neurodevelopmental processes taking place in the rostral brain. In this study, we investigated its impact on neocortical activity. We found that mice overexpressing Foxg1 in neocortical pyramidal cells displayed an electroencephalography (EEG) with increased spike frequency and were more prone to kainic acid (KA)-induced seizures. Consistently, primary cultures of neocortical neurons gain-of-function for Foxg1 were hyperactive and hypersynchronized. That reflected an unbalanced expression of key genes encoding for ion channels, gamma aminobutyric acid and glutamate receptors, and was likely exacerbated by a pronounced interneuron depletion. We also detected a transient Foxg1 upregulation ignited in turn by neuronal activity and mediated by immediate early genes. Based on this, we propose that even small changes of Foxg1 levels may result in a profound impact on pyramidal cell activity, an issue relevant to neuronal physiology and neurological aberrancies associated to FOXG1 copy number variations.
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Factores de Transcripción Forkhead/metabolismo , Neocórtex/fisiología , Proteínas del Tejido Nervioso/metabolismo , Células Piramidales/metabolismo , Animales , Variaciones en el Número de Copia de ADN , Electroencefalografía , Factores de Transcripción Forkhead/genética , Ratones , Proteínas del Tejido Nervioso/genética , Convulsiones/genética , Convulsiones/metabolismo , Regulación hacia ArribaRESUMEN
Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse models of ASD. We previously showed a reduced expression of GABAergic interneuron markers parvalbumin (PV) and somatostatin (SST) in the forebrain of adult mice lacking the Engrailed2 gene (En2-/- mice). Here, we extended this analysis to postnatal day (P) 30 by using in situ hybridization, immunohistochemistry, and quantitative RT-PCR to study the expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of En2-/- and wild type (WT) mice. In addition, GABA receptor subunit mRNA expression was investigated by quantitative RT-PCR in the same brain regions of P30 and adult En2-/- and WT mice. As observed in adult animals, PV and SST expression was decreased in En2-/- forebrain of P30 mice. The expression of GABA receptor subunits (including the ASD-relevant Gabrb3) was also altered in young and adult En2-/- forebrain. Our results suggest that GABAergic neurotransmission deficits are already evident at P30, confirming that neurodevelopmental defects of GABAergic interneurons occur in the En2 mouse model of ASD.
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Trastorno del Espectro Autista/patología , Neuronas GABAérgicas/patología , Regulación del Desarrollo de la Expresión Génica , Hipocampo/patología , Proteínas de Homeodominio/fisiología , Proteínas del Tejido Nervioso/fisiología , Receptores de GABA/metabolismo , Corteza Somatosensorial/patología , Animales , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/metabolismo , Modelos Animales de Enfermedad , Femenino , Neuronas GABAérgicas/metabolismo , Hipocampo/metabolismo , Interneuronas/metabolismo , Interneuronas/patología , Masculino , Ratones , Ratones Noqueados , Parvalbúminas/metabolismo , Corteza Somatosensorial/metabolismo , Somatostatina/metabolismoRESUMEN
Defective cortical processing of visual stimuli and altered retinal function have been described in autism spectrum disorder (ASD) patients. In keeping with these findings, anatomical and functional defects have been found in the visual cortex and retina of mice bearing mutations for ASD-associated genes. Here we sought to investigate the anatomy and function of the adult retina of Engrailed 2 knockout (En2-/-) mice, a model for ASD. Our results showed that En2 is expressed in all three nuclear layers of the adult retina. When compared to age-matched En2+/+ controls, En2-/- adult retinas showed a significant decrease in the number of calbindin+ horizontal cells, and a significant increase in calbindin+ amacrine/ganglion cells. The total number of ganglion cells was not altered in the adult En2-/- retina, as shown by Brn3a+ cell counts. In addition, En2-/- adult mice showed a significant reduction of photoreceptor (rhodopsin) and bipolar cell (Pcp2, PKCα) markers. Functional defects were also present in the retina of En2 mutants, as indicated by electroretinogram recordings showing a significant reduction in both a-wave and b-wave amplitude in En2-/- mice as compared to controls. These data show for the first time that anatomical and functional defects are present in the retina of the En2 ASD mouse model.
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Proteínas de Homeodominio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Retina/patología , Neuronas Retinianas/patología , Animales , Recuento de Células , Electrorretinografía , Proteínas de Homeodominio/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Retina/metabolismo , Neuronas Retinianas/metabolismoRESUMEN
Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2-/-) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENT Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 (En2-/- mice). Compared with WT controls, En2-/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.
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Complejo Nuclear Basolateral/fisiopatología , Miedo/fisiología , Proteínas del Tejido Nervioso/deficiencia , Corteza Somatosensorial/fisiopatología , Vibrisas/fisiología , Animales , Trastorno del Espectro Autista/psicología , Complejo Nuclear Basolateral/diagnóstico por imagen , Complejo Nuclear Basolateral/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Conectoma , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Conducta Alimentaria/fisiología , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Proto-Oncogénicas c-fos/análisis , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/patología , Tálamo/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Abnormal response to tactile stimulation, described as both hyper- and hypo-reactivity, is a common sensory impairment in multiple neuropsychiatric disorders. The neural bases of tactile sensitivity remain so far unknown. In the last years, animal studies have proven to be useful for shedding light on the cellular and molecular mechanism underlying sensory impairments. However, few behavioral tests have been developed in mice for assessing tactile perception abnormalities (e.g., the whisker nuisance [WN] test and the tactile prepulse inhibition assay). Here we provide a modified version of the WN test, which is based on the previously developed method by McNamara et al. (2010). The WN test permits to specifically detect tactile hypo/hyper-sensitivity relative to whisker stimulation in mice. The test starts with a habituation phase in which the mouse familiarizes itself with the experimental cage and the researcher/experimenter. After a sham session, the experimental session begins, consisting of bilateral whisker stimulation with a wooden stick. The advantages of using this protocol are many: it is relatively simple to set with no particular or expensive equipment needed, it is easily reproducible, it allows researchers to assess a variety of behavioral responses to a whisker-specific tactile perception in mice (i.e., fearful behavior, stance, hyperventilation, aggressive behavior and evasiveness) and provides important translational opportunities.
RESUMEN
Sensory abnormalities are commonly recognized as diagnostic criteria in autism spectrum disorder (ASD), as reported in the last edition of the Diagnostic and Statistical Manual of Mental Disorder (DSM-V). About 90% of ASD individuals have atypical sensory experiences, described as both hyper- and hypo-reactivity, with abnormal responses to tactile stimulation representing a very frequent finding. In this review, we will address the neurobiological bases of sensory processing in ASD, with a specific focus of tactile sensitivity. In the first part, we will review the most relevant sensory abnormalities detected in ASD, and then focus on tactile processing deficits through the discussion of recent clinical and experimental studies. In the search for the neurobiological bases of ASD, several mouse models have been generated with knockout and humanized knockin mutations in many ASD-associated genes. Here, we will therefore give a brief overview of the anatomical structure of the mouse somatosensory system, and describe the somatosensory abnormalities so far reported in different mouse models of ASD. Understanding the neurobiological bases of sensory processing in ASD mouse models may represent an opportunity for a better comprehension of the mechanisms underlying sensory abnormalities, and for the development of novel effective therapeutic strategies.
RESUMEN
The Engrailed-2 (En2) gene codes for a homeobox-containing transcription factor, involved in midbrain-hindbrain embryonic development. In postnatal brain, En2 is expressed in the ventral mesencephalon, cerebellum, hippocampus and neocortex. Two single-nucleotide polymorphisms (SNPs) that are associated to autism spectrum disorders (ASD) have been identified in the human EN2 gene. Accordingly, mice lacking the En2 homeodomain (En2hd/hd, referred to as En2-/-) show molecular, anatomical and behavioral "ASD-like" features. Among these, we previously showed a partial loss of GABAergic interneurons in the En2-/- postnatal hippocampus and neocortex, accompanied by a marked decrease of brain-derived neurotrophic factor (BDNF) signaling, a crucial determinant of GABAergic differentiation. In order to better investigate the role of En2 in GABAergic interneuron differentiation, we generated and subsequently differentiated neural stem cells (NSCs) from basal ganglia and neocortex of En2+/+ and En2-/- mouse embryos. Wild-type NSCs from both basal ganglia and neocortex express En2, while mutant ones do not, as expected. As compared to En2+/+ NSCs, En2-/- NSCs derived from basal ganglia show impaired GABAergic differentiation accompanied by a reduced expression of the BDNF receptor trkB. Conversely, En2-/- NSCs derived from the neocortex expressed high levels of trkB and readily differentiated into neurons, as En2+/+ NSCs. Our results suggest that En2 contributes to GABAergic neuron differentiation from basal ganglia NSCs through a trkB-dependent BDNF signaling, thus providing a possible explanation for the reduced number of GABAergic interneurons detected in the En2-/- postnatal forebrain.
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Ganglios Basales/metabolismo , Diferenciación Celular/fisiología , Neuronas GABAérgicas/metabolismo , Proteínas del Tejido Nervioso/deficiencia , Células-Madre Neurales/metabolismo , Animales , Femenino , Proteínas de Homeodominio/genética , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genéticaRESUMEN
Autism spectrum disorders (ASD) and epilepsy are common neurological diseases of childhood, with an estimated incidence of approximately 0.5-1% of the worldwide population. Several genetic, neuroimaging and neuropathological studies clearly showed that both ASD and epilepsy have developmental origins and a substantial degree of heritability. Most importantly, ASD and epilepsy frequently coexist in the same individual, suggesting a common neurodevelopmental basis for these disorders. Genome-wide association studies recently allowed for the identification of a substantial number of genes involved in ASD and epilepsy, some of which are mutated in syndromes presenting both ASD and epilepsy clinical features. At the cellular level, both preclinical and clinical studies indicate that the different genetic causes of ASD and epilepsy may converge to perturb the excitation/inhibition (E/I) balance, due to the dysfunction of excitatory and inhibitory circuits in various brain regions. Metabolic and immune dysfunctions, as well as environmental causes also contribute to ASD pathogenesis. Thus, an E/I imbalance resulting from neurodevelopmental deficits of multiple origins might represent a common pathogenic mechanism for both diseases. Here, we will review the most significant studies supporting these hypotheses. A deeper understanding of the molecular and cellular determinants of autism-epilepsy comorbidity will pave the way to the development of novel therapeutic strategies.
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Trastorno del Espectro Autista/fisiopatología , Excitabilidad Cortical/fisiología , Epilepsia/fisiopatología , Ácido Glutámico/fisiología , Inhibición Neural/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Trastorno del Espectro Autista/epidemiología , Comorbilidad , Epilepsia/epidemiología , HumanosRESUMEN
Social behavior is evolutionary conserved, and is thought to be evolved since it increased reproductive and survival fitness of living species. In humans, disturbances of social behavior are a peculiar pathological trait of neurodevelopmental disorders, namely autism spectrum disorder (ASD). ASD is defined by deficits in two core domains (social interaction/communication and repetitive/restrictive behaviors), which emerge during early postnatal development. ASD has a strong genetic component: copy number variations, de novo and familial mutations, as well as epigenetic modifications have been reported in a huge number of genes. Recent studies in mice demonstrate that mutations in a wide variety of ASD-associated genes can cause neurodevelopmental defects, which subsequently result in social behavior disturbances during early postnatal age and adulthood. From these studies, it clearly emerges that functionally interrelated cellular mechanisms underlie social behavior and its disturbances in ASD. Indeed, most of ASD-associated genes control neuronal differentiation and migration, growth of neuronal connections and synaptic function. Here we will present the recent advances in understanding the genetic determinants of social behavior, as they emerge from the study of ASD mouse models, and discuss the importance of these studies for the development of novel therapeutic approaches to overcome social disturbances in ASD.
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Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Conducta Social , Animales , RatonesRESUMEN
Autism spectrum disorders (ASD) are characterized by a high degree of genetic heterogeneity. Genomic studies identified common pathological processes underlying the heterogeneous clinical manifestations of ASD, and transcriptome analyses revealed that gene networks involved in synapse development, neuronal activity, and immune function are deregulated in ASD. Mouse models provide unique tools to investigate the neurobiological basis of ASD; however, a comprehensive approach to identify transcriptional abnormalities in different ASD models has never been performed. Here we used two well-recognized ASD mouse models, BTBR T(+) Itpr3 (tf) /J (BTBR) and Engrailed-2 knockout (En2 (-/-)), to identify conserved ASD-related molecular signatures. En2 (-/-) mice bear a mutation within the EN2 transcription factor homeobox, while BTBR is an inbred strain with unknown genetic defects. Hippocampal RNA samples from BTBR, En2 (-/-) and respective control (C57Bl/6J and En2 (+/+)) adult mice were assessed for differential gene expression using microarrays. A total of 153 genes were similarly deregulated in the BTBR and En2 (-/-) hippocampus. Mouse phenotype and gene ontology enrichment analyses were performed on BTBR and En2 (-/-) hippocampal differentially expressed genes (DEGs). Pathways represented in both BTBR and En2 (-/-) hippocampal DEGs included abnormal behavioral response and chemokine/MAP kinase signaling. Genes involved in abnormal function of the immune system and abnormal synaptic transmission/seizures were significantly represented among BTBR and En2 (-/-) DEGs, respectively. Interestingly, both BTBR and En2 (-/-) hippocampal DEGs showed a significant enrichment of ASD and schizophrenia (SCZ)-associated genes. Specific gene sets were enriched in the two models: microglial genes were significantly enriched among BTBR DEGs, whereas GABAergic/glutamatergic postsynaptic genes, FMRP-interacting genes and epilepsy-related genes were significantly enriched among En2 (-/-) DEGs. Weighted correlation network analysis (WGCNA) performed on BTBR and En2 (-/-) hippocampal transcriptomes together identified six modules significantly enriched in ASD-related genes. Each of these modules showed a specific enrichment profile in neuronal and glial genes, as well as in genes associated to ASD comorbidities such as epilepsy and SCZ. Our data reveal significant transcriptional similarities and differences between the BTBR and En2 (-/-) hippocampus, indicating that transcriptome analysis of ASD mouse models may contribute to identify novel molecular targets for pharmacological studies.
RESUMEN
Many evidences indicate that mice lacking the homeobox transcription factor engrailed-2 (En2(-/-) mice) represent a reliable model to investigate neurodevelopmental basis and gene expression changes relevant to autism spectrum disorders. Dysfunctions in fragile X mental retardation protein (FMRP), metabotropic glutamate receptor 5 (mGluR5), and GABAergic signaling pathways have been proposed as a possible pathogenic mechanism of autism spectrum disorders. Here, we exploited En2(-/-) mice to investigate hippocampal expression of FMRP, mGluR5, and GABA(A) receptor ß3 subunit (GABRB3). Quantitative reverse-transcription PCR showed that all these mRNAs were significantly downregulated in En2(-/-) mice compared with wild-type littermates. Western blot and immunohistochemistry confirmed the downregulation of FMRP and GABRB3 proteins, while showing a significant increase of mGluR5 protein in the En2(-/-) hippocampus. Our results suggest that the dysregulation of FMRP-mGluR5 signaling pathway, accompanied with a downregulation of GABRB3 expression, may contribute to the 'autistic-like' features observed in En2 mice, providing possible molecular targets for future pharmacological studies.