RGS4 deficit in prefrontal cortex contributes to the behaviors related to schizophrenia via system x_c^--mediated glutamatergic dysfunction in mice

Abstract

Rationale: Although molecular investigations of regulator of G-protein signaling 4 (RGS4) alterations in schizophrenia patients yielded partially inconsistent findings, the previous studies suggested that RGS4 is both a positional and functional candidate gene for schizophrenia and is significantly decreased in the prefrontal cortex. However, the exact role of RGS4 in the pathophysiology of schizophrenia is unclear. Moreover, a whole genome transcription profile study showed the possibility of RGS4-regulated expression of SLC7A11(xCT), a component of cysteine/glutamate transporter or system xc-. We hypothesized that system xc- is a therapeutic target of RGS4 deficit-mediated schizophrenia.Methods: Pharmacological and genetic manipulation of RGS4 in organotypic brain slice cultures were used as an ex vivo model to investigate its role in system xc- and glutamatergic function. Lentiviral-based mouse models with RGS4 deficit in the prefrontal cortex and treatment with system xc- activator, N-acetyl cysteine (NAC), were utilized to observe their impacts on glutamatergic function and schizophrenic behaviors.Results: Genetic and pharmacological inhibition of RGS4 resulted in a significant decrease in SLC7A11 (xCT) expression and hypofunction of system xc- and reduced glutamatergic function in organotypic brain slice cultures. However, NAC restored the dysregulation of RGS4-mediated functional deficits of glutamate. Moreover, knockdown of RGS4 specifically in the prefrontal cortex caused mice to exhibit behaviors related to schizophrenia such as increased stereotypy, impaired prepulse inhibition, deficits in social interactions, working memory, and nesting behavior, while enhancing sensitivity to the locomotor stimulatory effect of MK-801. These mice displayed glutamatergic dysfunction in the prefrontal cortex, which may have contributed to the behavioral deficits. RGS4 knockdown mice that received NAC treatment had improved glutamatergic dysfunction and schizophrenia behaviors.Conclusion: Our results suggest that RGS4 deficit induces dysregulation and dysfunction of system xc-, which further results in functional deficits of the glutamatergic system and subsequently to schizophrenia-related behavioral phenotypes. Activation of system xc- offers a promising strategy to treat RGS4 deficit-mediated schizophrenia.

MicroRNA-195 predicts olanzapine response in drug-free patients with schizophrenia: A prospective cohort study

“…The target genes of miR-195 predicted by bioinformatics are highly enriched in signaling pathways associated with neural junctions and synaptic plasticity, and these pathways are involved in the pathogenesis of SZ (Beveridge et al, 2010). Many of the predicted target genes of miR-195, such as RGS4, GRM7, GRIN3A, HTR2A, and PLXNA2, have been reported to correlate with SZ, providing evidence of a post-transcriptional mechanism that underlies SZ-associated glutamatergic and synaptic dysfunction (Huang et al, 2018; Tang et al, 2017; Yu et al, 2018b). For example, Mellios et al showed that miR-195 targets the 3′-untranslated region of BDNF in the human prefrontal cortex (PFC), resulting in downregulation of BDNF protein expression (Mellios et al, 2008).…”

G Protein-Coupled Estrogen Receptor 1 Knockout Deteriorates MK-801-Induced Learning and Memory Impairment in Mice

“…Thus, the subchronic model of SZ was utilized in this study. Moreover, the dose of MK-801 (0.6 mg/kg/day) was utilized in our previous research (Huang et al, 2018;Ding et al, 2019). Based on the hypothesis of this past study, we evaluated the effects of GPER1 deficiency on the hyperlocomotion, stereotypical behaviors, novel object recognition, social interaction, general activity, spatial learning, and the executive capability of the mouse subchronic model of SZ.…”

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

“…Furthermore, RGS4, RGS6, RGS7, and RGS20 can alter behavioral effects of opioids, with RGS4 and RGS20 promoting analgesic activity (28,(43)(44)(45)(46). RGS4, which has extensive distribution in regions of the brain (37,47), is implicated in a number of dopamine-related diseases, including schizophrenia (48,49), and has been a source of questions regarding its role in movement disorders (27,50,51). Driven by these examples of genetically-based observations, and others, small-molecule modulators of RGS protein function have emerged as attractive tools for more closely examining these processes using pharmacological methods.…”