Prenatal ontogeny as a susceptibility period for cortical GABA neuron disturbances in schizophrenia

Abstract

Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex (PFC). Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the PFC in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia.

Keywords: development; interneuron; parvalbumin; prefrontal cortex; somatostatin.

Figure 1. Schematic illustrating reported disturbances in PV and SST neurons in the PFC in schizophrenia

In the PFC of healthy human subjects (left panel), PV neurons (blue) are predominantly found in layers deep 3 and 4, while SST neurons (red) are predominantly localized to cortical layers 2, superficial 3, 5, and 6 and are also found in the superficial white matter (Hashimoto et al., 2003; Morris et al., 2008). In schizophrenia subjects (right panel), reduced mRNA levels of GAD67 and PV have been reported in PV neurons without a change in the number of PV neurons per tissue area (Hashimoto et al., 2003), suggesting incomplete phenotypic specification and/or maturation of PV neurons (lighter shade of blue) in the disorder. In contrast, a lower density of gray matter neurons that express detectable levels of SST mRNA has been reported in schizophrenia (Morris et al., 2008), which could reflect fewer gray matter SST neurons and/or neurons that do not express detectable levels of SST mRNA (lighter shade of red). Interestingly, some (Yang et al., 2011), though not all (Morris et al., 2008), studies have found a higher density of SST neurons in cortical white matter in the disorder, suggesting that the migration of some SST neurons may be arrested, leading to fewer SST neurons reaching their final destination in gray matter.

Figure 2. Figure illustrating some of the major roles of developmental regulators including ontogenetic transcriptional regulators, cytokine receptors, and other factors in various stages of development of cortical PV, SST, and calretinin neurons

This figure is based on published reports that largely utilized single, complete loss of gene function murine models. This list of factors is not exhaustive, and many of the factors may play additional roles beyond those listed here. Since many gene mutations are lethal postnatally, knowledge of the potential role of many factors in postnatal maturation and survival is not known. Full gene name and associated references: Arx: aristaless related homeobox (Colombo et al., 2007); COUP-TFII: chicken ovalbumin upstream promoter-transcription factor II (Kanatani et al., 2008; Reinchisi et al., 2012); CXCR4 and CXCR7: chemokine (C-X-C motif) receptors 4 and 7 (Wang et al., 2011; Sanchez-Alcaniz et al., 2011; Meechan et al., 2012); Dlx1: Distal-less homeobox 1 (Cobos et al., 2005); Dlx5/6: Distal-less homeobox 5/6 (Wang et al., 2010); ErbB4: receptor tyrosine-protein kinase erbB-4 (Flames et al., 2004; Fazzari et al., 2010; Ting et al., 2011); Gsx2: genomic screened homeobox 2 (Fogarty et al., 2007); Lhx6: LIM homeodomain factor 6 (Liodis et al., 2007; Zhao et al., 2008; Neves et al., 2012); Nkx2.1: NK2 homebox 1 (Sussel et al., 1999; Xu et al., 2004; Butt et al., 2008; Nobrega-Pereira et al., 2008); Nkx6.2: NK6 homeobox 2 (Fogarty et al., 2007); SATB1: Special AT-rich DNA Binding Protein 1 (Denaxa et al., 2012); Sox6: SRY (sex determining region Y)-box 6 (Azim et al., 2009; Batista-Brito et al., 2009); Zeb2/Sip1/Zfhx1b: zinc finger E-box binding homeobox 2 (van, V et al., 2013; McKinsey et al., 2013).