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    • We also found that the size of mEPSC

    2023-10-10

    We also found that the size of mEPSC amplitude was reduced in unc-43 mutants, consistent with the decrease in synaptic GLR-1/GLR-2 heteromeric receptors. The decrease in mEPSC amplitude was not as great as that observed when measuring current in response to pressure application of glutamate. These differences are not directly comparable because pressure application activates both synaptic and extrasynaptic classes of glutamate receptors, whereas mEPSCs represent current mediated by the synaptic population only. Although GLR-1/GLR-2 heteromeric receptors are greatly reduced in unc-43 mutants, those that do reach synapses by diffusion might preferentially localize to the postsynaptic membrane, perhaps because of greater affinity for the underlying scaffolding machinery, thus explaining the smaller decrease in mEPSC amplitude. Diffusion of receptors is slow and inefficient, but over many days of development receptors can populate distant synapses. What is especially deficient in unc-43 mutants is the ability to mount rapid changes in receptor number. Our results from FRAP, photoconversion, and plasticity experiments, demonstrated that unc-43 mutants were deficient in their response to perturbations that required rapid changes in synaptic receptors. Thus, CaMKII is essential for the dynamic control of receptor number at synapses.
    Experimental Procedures
    Acknowledgments We thank members of the A.V.M. laboratory for comments on the manuscript, Dane Maxfield and Aleksander Maricq for help with MATLAB analysis, Linda Hauth for generating transgenic strains, Mark Hauth for technical assistance and the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and Kang Shen for providing worm strains. This research was made possible by support from NIH Grants NS35812 and DA035080 (A.V.M.) and by postdoctoral fellowships from the Swiss National Science Foundation (F.J.H.).
    Introduction The DTNBP1 gene has generated much interest due to its link to schizophrenia following a seminal Irish family-based association analysis (Straub et al., 2002). While dysbindin expression was found to be reduced in the hippocampus and cortex of schizophrenia patients (Talbot et al., 2004, Tang et al., 2009a, Weickert et al., 2008), how dysbindin modulates the pathogenesis of the disease remains unclear. While schizophrenia has often been modeled as a neurodevelopmental disorder (Rapoport et al., 2005), several lines of evidence suggest that dysbindin may have a role in ABT263 development. Imaging studies in children found that genetic variation in DTNBP1 was associated with changes in gray and white brain matter volume (Tognin et al., 2011) and hyper-activation of particular regions during visual processing (Mechelli et al., 2010). In rodents, dysbindin expression is highest during embryonic stages (Ghiani et al., 2010, Ito et al., 2010) while reduction of dysbindin in cultured neurons led to abnormalities in neurite growth and dendritic morphology (Ghiani et al., 2010, Ito et al., 2010, Kubota et al., 2009, Ma et al., 2011). Dysbindin is likely involved in protein trafficking along the endosomal–lysosomal pathway (Di Pietro et al., 2006, Gokhale et al., 2012, Larimore et al., 2011) as it was shown to be a component of the biogenesis of lysosome-related organelles (BLOC)-1 complex (Li et al., 2003, Starcevic and Dell'Angelica, 2004) and to interact with the adaptor-protein 3 (AP-3) complex (Hikita et al., 2009, Taneichi-Kuroda et al., 2009). Dysbindin has been shown to modulate the membrane surface expression of at least two receptor classes, NMDAR (T.T. Tang et al., 2009) and D2R (Iizuka et al., 2007, Ji et al., 2009, Marley and von Zastrow, 2010). Besides a potential role in development and receptor trafficking, fractionation studies with human tissue revealed that dysbindin was present in hippocampal synapses suggesting a role in neurotransmission (Talbot et al., 2004, Talbot et al., 2011). Magnetic resonance imaging revealed that a mouse model lacking dysbindin due to a spontaneous deletion in the DTNBP 1 gene (Li et al., 2003), named sandy, displayed alterations in hippocampal activity (Lutkenhoff et al., 2012). This is consistent with studies reporting altered glutamatergic transmission in acute brain slices from the sandy mice (Chen et al., 2008, Tang et al., 2009b). Whether these defects represent primary or secondary consequences, due to compensatory mechanism expression, remains unclear. No electrophysiology studies have been performed in primary neurons from sandy mice where cell autonomous phenotypes can be identified. To explore whether dysbindin affects fast glutamatergic synaptic transmission mediated by the AMPAR classes of receptors, we first analyzed hippocampal cultures prepared from sandy animals lacking dysbindin expression and uncovered a previously unidentified defect in AMPAR function. We also found that loss of dysbindin led to enhanced CA3–CA1 AMPAR-mediated synaptic transmission and long term plasticity in acute hippocampal slices from juvenile animals. Altogether, these findings suggest that dysbindin expression may affect hippocampal based cognitive processes by influencing AMPAR function during juvenile brain development.