Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia

Abstract

Schizophrenia, a major psychiatric disorder defined by delusions and hallucinations, among other symptoms, often with onset in early adulthood, is potentially associated with molecular and cellular alterations in parvalbumin-expressing fast spiking interneurons and other constituents of the cortical inhibitory GABAergic circuitry. The underlying mechanisms, including the role of disease-associated risk factors operating in adolescence such as drug abuse and social stressors, remain incompletely understood. Here, we summarize emerging findings from animal models, highlighting the ability of parvalbuminergic interneurons (PVI) to induce, during the juvenile period, long-term plastic changes in prefrontal and visual cortex, thereby altering perception, cognition and behavior in the adult. Of note, molecular alterations in PVI from subjects with schizophrenia, including downregulated expression of a subset of GABAergic genes, have also been found in juvenile stress models of the disorder. Some of the transcriptional alterations observed in schizophrenia postmortem brain could be linked to changes in the epigenetic architecture of GABAergic gene promoters, including dysregulated DNA methylation, histone modification patterns and disruption of promoter-enhancer interactions at site of chromosomal loop formations. Therefore, we predict that, in the not-to-distant future, PVI- and other cell-type specific epigenomic mappings in the animal model and human brain will provide novel insights into the pathophysiology of schizophrenia and related psychotic diseases, including the role of cortical GABAergic circuitry in shaping long-term plasticity and cognitive function of the cerebral cortex.

Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity

“…For instance, studies have documented disruptions in the development or maturation of fast-spiking (FS) interneurons in the pathophysiology underlying disorders like schizophrenia (Lewis, Hashimoto, & Volk, 2005; Morishita, Kundakovic, Bicks, Mitchell, & Akbarian, 2015). Similarly, one of the primary pathologies in attention-deficit disorder is a delay in normal white matter development.…”

Cortical interneuron specification: the juncture of genes, time and geometry

“…Thus, it seems inevitable that further investigation will provide additional examples of transcription factors that have different affects depending on what portion of the genome is accessible in a given cell. Epigenetic changes in interneurons might also contribute to psychiatric diseases, as epigenetic dysregulation at GABAergic promotors in PV cells is associated with schizophrenia [62]. More work needs to be done to understand the molecular mechanisms regulating GE development, particularly: how cell cycle dynamics and mode of division influence cell fate; what contribution, if any, does lineage have on subtype specification; what are the epigenetic mechanisms regulating cell fate decisions; and how does early network activity modify intrinsic genetic programs in various interneuron subtypes?…”

Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats

“…We hypothesized, that epigenetic changes as some particular DNA and histone modifications, may contribute to the development of SCZ-like symptoms in this animal model. We focused on the frontal part of the brain (FB) as the main area thought to be involved in SCZ [47] and associated mostly with epigenetic changes in this disorder [14,48,49]. However, the current literature does suggest that alterations are not isolated to a few brain regions, but are characterized by abnormalities within brain networks [50], like the hippocampo-prefrontal cortex (PFC) system [51].…”