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

https://doi.org/10.1016/j.nlm.2015.03.005Get rights and content

Highlights

  • GABAergic and Parvalbuminergic interneurons (PVIs) are disrupted in schizophrenia.

  • PVIs mediate juvenile plasticity and provide long-lasting impact on adult behaviors.

  • Epigenetic alterations in GABAergic genes are found in schizophrenia brains.

  • Epigenomic mapping of PVI is expected to provide novel insights into pathophysiology.

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.

Introduction

Schizophrenia (SCZ), a mental disorder associated with delusions, hallucinations, disorganized thought, social withdrawal and various other symptoms is not defined by unifying neuropathology (Catts et al., 2013, Dorph-Petersen and Lewis, 2011) or narrowly defined genetic risk architectures (Andreassen et al., 2014, Rodriguez-Murillo et al., 2012). However, clinical and preclinical research is beginning to identify major building blocks that contribute to the complex pathophysiology of SCZ. One such building block is the GABAergic circuitry in the cerebral cortex. GABAergic interneurons provide a major and critical source of inhibition to cortical networks, as animal models of disrupted GABAergic signaling show deficits in cortical plasticity (Fagiolini et al., 2004, Hensch, 2005, Hensch et al., 1998, Iwai et al., 2003, Katagiri et al., 2007), synchronous oscillations (Gonzalez-Burgos et al., 2011, Lodge et al., 2009) and cognition (Gonzalez-Burgos et al., 2011, Gruber et al., 2010). Importantly, similar phenotypes are encountered in SCZ (Gonzalez-Burgos et al., 2011, Inan et al., 2013, Lewis et al., 2005). GABAergic interneurons, however, are an extremely diverse population that can be molecularly classified into three non-overlapping groups based on the expression of either Parvalbumin (PV), Somatostatin (SST) or serotonin receptor 3a (5-HT3AR) that together encompass nearly 100% of all cortical interneurons (Rudy, Fishell, Lee, & Hjerling-Leffler, 2011). Among these subpopulations, fast-spiking interneurons expressing PV provide inhibition to the cell bodies of pyramidal neurons to control their output. This inhibition influences rhythmic synchrony and facilitates information processing during cognitive tasks. Importantly, molecular alterations in PV interneurons (PVI) have been reported in prefrontal cortex and other cortical areas of SCZ subjects (Fung et al., 2010, Mellios et al., 2009, Volk and Lewis, 2013), including downregulated expression of GABA synthesis enzyme GAD1/GAD67 (Hashimoto et al., 2003), potassium channel subunits (Georgiev et al., 2014) and transcription factors (Volk et al., 2012a), among various others (Volk, Chitrapu, Edelson, & Lewis, 2014). In addition to PV, low-threshold spiking SST + neurons also demonstrate altered gene expression in SCZ cortex and hippocampus (Akbarian and Huang, 2006, Fung et al., 2014, Fung et al., 2010, Konradi et al., 2011, Mellios et al., 2009, Schmidt and Mirnics, 2012). According to some estimates, up to 30–40% of subjects with schizophrenia show robust decreases in expression in a subset of RNAs specifically expressed in GABA neurons (Volk et al., 2012b). The underlying mechanisms of GABAergic deficits, just like SCZ as a disorder, are complex and heterogeneous. However, functional hypoactivity and a decrease in neurotrophin levels and signaling are likely to be important drivers for the observed deficits in GABAergic gene expression (Akbarian and Huang, 2006, Hashimoto et al., 2005, Thompson Ray et al., 2011).

Section snippets

Role of PVIs in the postnatal maturation of cortical circuits

Cortical PVIs show a protracted developmental trajectory across adolescence (Hoftman and Lewis, 2011, O’Donnell, 2011). In prefrontal cortex, a brain region frequently affected by dysfunction and hypoactivity in subjects with SCZ, preclinical work strongly points to a period of heightened sensitivity of PVI during postnatal development (including childhood and juvenile stages). Disruption during this period results in subsequent deviation from the normal course of development into maladaptive

Epigenetic regulation in cortical interneurons

The regulatory networks governing the molecular architectures of cortical inhibitory circuitry are exceedingly complex and include a diverse array of transcriptional and post-transcriptional mechanisms. To mention just one recent example from the SCZ literature, prefrontal deficits in the expression of a subset of GABA neuron-specific mRNAs were found to be dependent on the regional supply of Brain-derived Neurotrophic Factor (BDNF), which in turn was subject to post-transcriptional control by

Acknowledgments

Work in the authors’ laboratories is supported by the National Institutes of Health and the Brain Behavior Research Foundation.

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