RESUMEN
In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes.
Asunto(s)
Conducta Animal/efectos de los fármacos , Corteza Cerebelosa/efectos de los fármacos , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Cognición/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Conducta Social , Ácido Valproico/análogos & derivados , Acetilación , Animales , Corteza Cerebelosa/enzimología , Trastornos Generalizados del Desarrollo Infantil/inducido químicamente , Trastornos Generalizados del Desarrollo Infantil/enzimología , Trastornos Generalizados del Desarrollo Infantil/psicología , Modelos Animales de Enfermedad , Femenino , Histonas/metabolismo , Ácidos Hidroxámicos/farmacología , Masculino , Exposición Materna , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas Wistar , Ácido Valproico/farmacología , VorinostatRESUMEN
In utero exposure of rodents to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Trastornos del Conocimiento/prevención & control , Modelos Animales de Enfermedad , Histona Desacetilasa 1/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/uso terapéutico , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Ácidos Siálicos/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Niño , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Trastornos Generalizados del Desarrollo Infantil/patología , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Trastornos del Conocimiento/etiología , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/patología , Femenino , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/toxicidad , Humanos , Masculino , Terapia Molecular Dirigida , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Neuronas/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Conducta SocialRESUMEN
Given that suppressed reelin protein synthesis is associated with cognitive dysfunction in both rodents and humans, we examined the ontogeny of these deficits in rats reared in isolation as a basis for understanding developmental emergence of neuropsychiatric illness. Isolation rearing exerted minimal effects on spatial learning other than to inhibit the transient learning improvement observed in social reared rats at postnatal day 60. By contrast, at postnatal day 80, animals reared in isolation were significantly impaired in an avoidance conditioning paradigm, a deficit that correlated with suppressed reelin synthesis restricted to the ventral aspect of the dentate gyrus. These findings suggest that environmental factors alone can impair forms of cognitive development with relevant region-specific dysfunctional plasticity.
Asunto(s)
Reacción de Prevención/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Condicionamiento Clásico/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Discapacidades para el Aprendizaje/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Serina Endopeptidasas/metabolismo , Aislamiento Social , Envejecimiento , Animales , Moléculas de Adhesión Celular Neuronal/biosíntesis , Giro Dentado/metabolismo , Proteínas de la Matriz Extracelular/biosíntesis , Masculino , Aprendizaje por Laberinto/fisiología , Proteínas del Tejido Nervioso/biosíntesis , Ratas , Ratas Wistar , Proteína Reelina , Serina Endopeptidasas/biosíntesis , Percepción Espacial/fisiología , Factores de TiempoRESUMEN
The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.