RESUMEN
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.
Asunto(s)
Corteza Cerebral/metabolismo , Regulación de la Expresión Génica/fisiología , Aislamiento Social/psicología , Animales , Conducta Animal/fisiología , Corteza Cerebral/química , Corteza Cerebral/ultraestructura , Biología Computacional , ADN/biosíntesis , ADN/genética , Masculino , Microdiálisis , Actividad Motora/fisiología , Familia de Multigenes , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/biosíntesis , ARN/genética , ARN Complementario/biosíntesis , ARN Complementario/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés Psicológico/genética , Estrés Psicológico/psicología , Sinapsis/fisiología , Factores de TranscripciónRESUMEN
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.