Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein knockout mice.

Akito Nakao,Hirotaka Shoji,Takafumi Miki,Tsuyoshi Miyakawa,Yasuo Mori,Hiroshi Takeshima,Miyuki Nishi

doi:10.3389/fnbeh.2015.00141

Abstract

Calcium (Ca2+) influx through voltage-gated Ca2+ channels (VGCCs) induces numerous intracellular events such as neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation. It has been shown that genes related to Ca2+ signaling, such as the CACNA1C, CACNB2, and CACNA1I genes that encode VGCC subunits, are associated with schizophrenia and other psychiatric disorders. Recently, VGCC beta-anchoring and -regulatory protein (BARP) was identified as a novel regulator of VGCC activity via the interaction of VGCC β subunits. To examine the role of the BARP in higher brain functions, we generated BARP knockout (KO) mice and conducted a comprehensive battery of behavioral tests. BARP KO mice exhibited greatly reduced locomotor activity, as evidenced by decreased vertical activity, stereotypic counts in the open field test, and activity level in the home cage, and longer latency to complete a session in spontaneous T-maze alteration test, which reached “study-wide significance.” Acoustic startle response was also reduced in the mutants. Interestingly, they showed multiple behavioral phenotypes that are seemingly opposite to those seen in the mouse models of schizophrenia and its related disorders, including increased working memory, flexibility, prepulse inhibition, and social interaction, and decreased locomotor activity, though many of these phenotypes are statistically weak and require further replications. These results demonstrate that BARP is involved in the regulation of locomotor activity and, possibly, emotionality. The possibility was also suggested that BARP KO mice may serve as a unique tool for investigating the pathogenesis/pathophysiology of schizophrenia and related disorders. Further evaluation of the molecular and physiological phenotypes of the mutant mice would provide new insights into the role of BARP in higher brain functions.

Highlights

In calcium (Ca2+) signaling pathways, voltage-gated calcium channels (VGCCs) initiate numerous intracellular events including neuronal excitability, neurotransmitter release, synaptic plasticity, and Ca2+-induced gene regulation (Catterall, 2011)
We found that beta-anchoring and -regulatory protein (BARP) KO mice have hypo-locomotor activity as evidenced by decreased vertical activity, stereotypic counts in the open field test, and activity level in the home cage, and longer latency to complete a session in spontaneous T-maze alteration test, which reached “study-wide significance.”
Some suggestive evidence showed that BARP KO mice may have increased anxiety-like behavior and multiple behavioral phenotypes that are seemingly opposite to those seen in the mouse models of schizophrenia and its related disorders

Summary

Introduction

In calcium (Ca2+) signaling pathways, voltage-gated calcium channels (VGCCs) initiate numerous intracellular events including neuronal excitability, neurotransmitter release, synaptic plasticity, and Ca2+-induced gene regulation (Catterall, 2011). Several studies have demonstrated that the β4 subunit directly regulates activity-dependent gene regulation (Subramanyam et al, 2009; Tadmouri et al, 2012). In this context, the β4 subunit binds to a transcription factor for DNA binding, a phosphatase for histone dephosphorylation, and heterochromatin protein 1γ for nucleosome association (Hibino et al, 2003; Xu et al, 2011; Tadmouri et al, 2012). BARP modulates the localization of β subunits and their association with the α1 subunit to negatively regulate VGCC activity (Béguin et al, 2014)

Methods

Results

Conclusion