Modulation of behavioral networks by selective interneuronal inactivation

Abstract

Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region-specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes, whereas suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…CCK þ interneurons are the only interneuron cell type that expresses the cannabinoid receptor CNR1 (Eggan et al, 2010), which silences CCK þ interneurons (Losonczy et al, 2004) and disrupts the hippocampus (Hajos et al, 2000;Katona et al, 1999) and amygdala (Katona et al, 2001;Tan et al, 2010) function. Furthermore, GAD1 suppression in CCK þ /CNR1 þ interneurons leads to dysfunctional amygdala-dependent behavior and aminergic signaling Schmidt et al, 2013). Finally, mild stress during development results in epigenetic-mediated reduction of dopaminergic cell function in DISC1 mutant mice (Niwa et al, 2013), whereas the loss of DISC1 in the frontal cortex of adult rats increased stress sensitivity and resulted in cognitive impairments that were not observed in rats with normal DISC1 expression (Gamo et al, 2013).…”

“…During adolescence, when cells have finished migrating and cortical circuits are maturing, GAD1 suppression decreases axonal branching in PV þ cells in a cell autonomous manner (Chattopadhyaya et al, 2007) and increases pyramidal cell activity (Lazarus et al, 2013). 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).…”

“…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).…”

Human dermal fibroblasts in psychiatry research

“…Considering that the brain pathophysiology of psychiatric disorders can be only analyzed in humans by non-invasive methods, animal models are the preferred choice to examine behavioral disturbances and associated structural and functional brain alterations that arise from genetic manipulations (Brown et al, 2015; Schmidt et al, 2014; Schmidt and Mirnics, 2012). Although these experiments are essential, psychiatric disorders are uniquely human conditions, and cannot be interpreted in the disease context without understanding the events in the diseased tissue (Nestler and Hyman, 2010).…”

Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia

“…Genetic engineering-induced GAD1/GAD67 deficiency in cortical interneurons is detrimental for neuronal signaling and cognition and social interactions (Belforte et al, 2010; Chattopadhyaya et al, 2007; Lazarus et al, 2013; Schmidt et al, 2014). Whether or not an experimentally induced increase in Gad1/Gad67 would elicit therapeutic effects in preclinical SCZ models remains to be determined.…”