Modeling Interneuron Dysfunction in Schizophrenia

Abstract

Schizophrenia is a debilitating neurodevelopmental disorder affecting approximately 1% of the population and imposing a significant burden on society. One of the most replicated and well-established postmortem findings is a deficit in the expression of the gene encoding the 67-kDa isoform of glutamic acid decarboxylase (GAD67), the primary GABA-producing enzyme in the brain. GAD67 is expressed in various classes of interneurons, with vastly different morphological, molecular, and physiological properties. Importantly, GABA system deficits in schizophrenia encompass multiple interneuronal subtypes, raising several important questions. First, do different classes of interneurons regulate different aspects of behavior? Second, can we model cell-type-specific GABAergic deficits in mice, and will the rodent findings translate to human physiology? Finally, will this knowledge open the door to knowledge-based approaches to treat schizophrenia?

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Adult mice with GAD1 gene expression deficits in restricted interneuron populations have distinct molecular and behavioral dysfunction depending on the affected cell type Kvitsiani et al, 2013;Schmidt et al, 2013). These data provide functional context to postmortem studies that consistently implicate diverse interneuron cell types in schizophrenia (Hashimoto et al, 2003(Hashimoto et al, , 2008aHoftman et al, 2013;Iritani et al, 2000;Kuromitsu et al, 2001;Maldonado-Aviles et al, 2009;Mellios et al, 2009;Morris et al, 2008;Volk et al, 2012) and suggest that GABAergic gene expression deficits seen in post-mortem studies of patients with schizophrenia actively contribute to important aspects of brain development and behavior (Lewis et al, 2005;Marin, 2012;Schmidt and Mirnics, 2012).…”

“…Since the initial description of the neurodevelopmental hypothesis of schizophrenia, data from epidemiological, clinical, post-mortem, and animal model studies continue to support and extend its premise (Brandon and Sawa, 2011;Brown, 2011;Horvath and Mirnics, 2014a, b;Lewis and Levitt, 2002;Lewis and Mirnics, 2006;Michel et al, 2012;Mirnics et al, 2000Mirnics et al, , 2001bMirnics et al, , 2006Mirnics and Lewis, 2001a;Rapoport et al, 2012;Schmidt and Mirnics, 2012). Concurrently, GABAergic dysfunction has become recognized as a hallmark feature of the disorder.…”

“…In fact, our understanding of the developmental importance of the GABAergic system comes largely from transgenic mouse research. Simply put, while there are no (and perhaps never will be) 'true' rodent models of schizophrenia or 'schizophrenic mice', a combined use of transgenic technology and environmental challenges in rodent models is essential for understanding genes, cognition, and mental disorders Garbett et al, 2010Garbett et al, , 2012Jaaro-Peled et al, 2009;Levitt, 2005;Papaleo et al, 2012;Schmidt et al, 2013;Schmidt and Mirnics, 2012;Smith et al, 2007).…”

Developmental Age Differentially Mediates the Calcium-Binding Protein Parvalbumin in the Rat: Evidence for a Selective Decrease in Hippocampal Parvalbumin Cell Counts

“…ketamine, MK-801) in rodents, as this model has shown changes in PV expression comparable to those seen in human postmortem tissue, in addition to alterations in cognitive performance [for reviews, see [33,34,35]]. However, these studies have revealed conflicting results with regard to whether the NMDA hypofunction model produces changes in PV immunoreactivity quantified by either immunohistochemical staining and/or protein assays.…”

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

“…Importantly, molecular alterations in PV interneurons (PVI) have been reported in prefrontal cortex and other cortical areas of SCZ subjects (Fung, Webster, Sivagnanasundaram, Duncan, Elashoff, and Weickert, 2010; Mellios, Huang, Baker, Galdzicka, Ginns, and Akbarian, 2009; Volk and Lewis, 2013), including downregulated expression of GABA synthesis enzyme GAD1/GAD67 (Hashimoto, Volk, Eggan, Mirnics, Pierri, Sun, Sampson, and Lewis, 2003), potassium channel subunits (Georgiev, Arion, Enwright, Kikuchi, Minabe, Corradi, Lewis, and Hashimoto, 2014) and transcription factors (Volk, Matsubara, Li, Sengupta, Georgiev, Minabe, Sampson, Hashimoto, and Lewis, 2012a), among various others (Volk, Chitrapu, Edelson, and 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, Fillman, Webster, and Shannon Weickert, 2014; Fung et al, 2010; Konradi, Yang, Zimmerman, Lohmann, Gresch, Pantazopoulos, Berretta, and Heckers, 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, Matsubara, Li, Sengupta, Georgiev, Minabe, Sampson, Hashimoto, and Lewis, 2012b).…”