Comprehensive Behavioral Phenotyping of Ryanodine Receptor type 3 (RyR3) Knockout Mice: Decreased Social Contact Duration in Two Social Interaction Tests

Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University Toyoake, Japan.
Frontiers in Behavioral Neuroscience (Impact Factor: 4.16). 02/2009; 3:3. DOI: 10.3389/neuro.08.003.2009
Source: PubMed

ABSTRACT Dynamic regulation of the intracellular Ca2+ concentration is crucial for various neuronal functions such as synaptic transmission and plasticity, and gene expression. Ryanodine receptors (RyRs) are a family of intracellular calcium release channels that mediate calcium-induced calcium release from the endoplasmic reticulum. Among the three RyR isoforms, RyR3 is preferentially expressed in the brain especially in the hippocampus and striatum. To investigate the behavioral effects of RyR3 deficiency, we subjected RyR3 knockout (RyR3-/-) mice to a battery of behavioral tests. RyR3-/- mice exhibited significantly decreased social contact duration in two different social interaction tests, where two mice can freely move and make contacts with each other. They also exhibited hyperactivity and mildly impaired prepulse inhibition and latent inhibition while they did not show significant abnormalities in motor function and working and reference memory tests. These results indicate that RyR3 has an important role in locomotor activity and social behavior.

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Available from: Keizo Takao, Jul 21, 2015
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    • "Spatial learning is tightly correlated with selective upregulation of RyR expression (Adasme et al. 2011; Cavallaro et al. 1997; Yang et al. 2009; Zhao et al. 2000). Targeted deletion of RyR3 in mice causes impairments in social behavior (Matsuo et al. 2009) and deficits in contextual fear conditioning but improves spatial learning in the Morris water maze task (Futatsugi et al. 1999; Kouzu et al. 2000), whereas selective knockdown of RyR2 and RyR3 impairs avoidance memory processes (Galeotti et al. 2008). Previous studies have implicated a local release of Ca 2+ from intracellular stores in the maintenance of dendrites (Lohmann et al. 2002), the regulation of the motility of dendritic filopodia (Lohmann et al. 2005), and the increased size of dendritic spines (Korkotian and Segal 1999). "
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    ABSTRACT: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) promote dendritic growth in hippocampal neurons via ryanodine receptor (RyR)-dependent mechanisms; however, downstream signaling events that link enhanced RyR activity to dendritic growth are unknown. Activity-dependent dendritic growth, which is a critical determinant of neuronal connectivity in the developing brain, is mediated by calcium ion (Ca(2+))-dependent activation of Ca(2+)/calmodulin kinase-I (CaMKI), which triggers cAMP response element binding protein (CREB)-dependent Wnt2 transcription. RyRs regulate the spatiotemporal dynamics of intracellular Ca(2+) signals, but whether RyRs promote dendritic growth via modulation of this signaling pathway is not known. We tested the hypothesis that the CaMKI-CREB-Wnt2 signaling pathway couples NDL PCB-enhanced RyR activity to dendritic arborization. Ca(2+) imaging of dissociated cultures of primary rat hippocampal neurons indicated that PCB-95 (2,2',3,5'6-pentachlorobiphenyl; a potent RyR potentiator), enhanced synchronized Ca(2+) oscillations in somata and dendrites that were blocked by ryanodine. As determined by Western blotting and quantitative polymerase chain reaction, PCB-95 also activated CREB and up-regulated Wnt2. Blocking CaMKK, CaMKIα/γ, MEK/ERK, CREB, or Wnt2 prevented PCB-95-induced dendritic growth. Antagonism of γ-aminobutyric acid (GABA) receptors with bicuculline (BIC) phenocopied the dendrite-promoting effects of PCB-95, and pharmacological antagonism or siRNA knockdown of RyR blocked BIC-induced dendritic growth in dissociated and slice cultures of hippocampal neurons. RyR activity contributes to dynamic remodeling of dendritic architecture in response to NDL PCBs via CaMKI-CREB-Wnt2 signaling in rats. Our findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling associated with autism.
    Environmental Health Perspectives 04/2012; 120(7):1003-9. DOI:10.1289/ehp.1104833 · 7.03 Impact Factor
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    • "We compared in vivo muscle strength in 4–5-mo-old male WT and IT/+ mice using both hanging task (Fig. 1 A) (Ogura et al., 2001) and grip strength (Fig. 1 B) (Brooks and Dunnett, 2009; Matsuo et al., 2009) tests. Grip strength and hanging tasks were used because performance in these tasks depends strongly on flexion of the digits, which involves the FDB and interosseous muscles used to assess EC coupling and RYR1 release channel function in subsequent single-fiber experiments (Figs. "
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    ABSTRACT: The type 1 isoform of the ryanodine receptor (RYR1) is the Ca(2+) release channel of the sarcoplasmic reticulum (SR) that is activated during skeletal muscle excitation-contraction (EC) coupling. Mutations in the RYR1 gene cause several rare inherited skeletal muscle disorders, including malignant hyperthermia and central core disease (CCD). The human RYR1(I4898T) mutation is one of the most common CCD mutations. To elucidate the mechanism by which RYR1 function is altered by this mutation, we characterized in vivo muscle strength, EC coupling, SR Ca(2+) content, and RYR1 Ca(2+) release channel function using adult heterozygous Ryr1(I4895T/+) knock-in mice (IT/+). Compared with age-matched wild-type (WT) mice, IT/+ mice exhibited significantly reduced upper body and grip strength. In spite of normal total SR Ca(2+) content, both electrically evoked and 4-chloro-m-cresol-induced Ca(2+) release were significantly reduced and slowed in single intact flexor digitorum brevis fibers isolated from 4-6-mo-old IT/+ mice. The sensitivity of the SR Ca(2+) release mechanism to activation was not enhanced in fibers of IT/+ mice. Single-channel measurements of purified recombinant channels incorporated in planar lipid bilayers revealed that Ca(2+) permeation was abolished for homotetrameric IT channels and significantly reduced for heterotetrameric WT:IT channels. Collectively, these findings indicate that in vivo muscle weakness observed in IT/+ knock-in mice arises from a reduction in the magnitude and rate of RYR1 Ca(2+) release during EC coupling that results from the mutation producing a dominant-negative suppression of RYR1 channel Ca(2+) ion permeation.
    The Journal of General Physiology 01/2011; 137(1):43-57. DOI:10.1085/jgp.201010523 · 4.57 Impact Factor
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    • "The viability of the general RyR3 knockout mouse, in contrast to the RyR1 and RyR2 knockout mice [1] [2] [104], has resulted in many studies characterizing the neurological phenotype of these mice. The RyR3 deficient mice exhibit decreased social behavior [105] and two times greater locomotor activity [104] that is associated with the tendency to run in circular motions [6]. Striatum from these mice release less dopamine when challenged with low concentration ryanodine, which activates ryanodine receptors, suggesting the possibility that the effect of RyR3 on locomotion may be related to its role in the basal ganglia [106]. "
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    ABSTRACT: Ryanodine receptors (RyR) regulate intracellular Ca(2+) release in many cell types and have been implicated in a number of inherited human diseases. Over the past 15 years genetically engineered mouse models have been developed to elucidate the role that RyRs play in physiology and pathophysiology. To date these models have implicated RyRs in fundamental biological processes including excitation-contraction coupling and long term plasticity as well as diseases including malignant hyperthermia, cardiac arrhythmias, heart failure, and seizures. In this review we summarize the RyR mouse models and how they have enhanced our understanding of the RyR channels and their roles in cellular physiology and disease.
    FEBS letters 03/2010; 584(10):1956-65. DOI:10.1016/j.febslet.2010.03.005 · 3.34 Impact Factor
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