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