Molecular neuroscienceDistinct roles for spinophilin and neurabin in dopamine-mediated plasticity
Section snippets
Gene targeting and strain development
Generation of the spinophilin KO was described previously (Feng et al., 2000). Mutation of the neurabin gene was performed essentially using the methodology of Wattler et al. (1999). Using a PCR strategy with primers derived from a 5′ EST, four overlapping genomic clones spanning 14 kb were isolated from a lambda KOS library. Each genomic insert was flanked by the negative selection marker, tk, and contained bacterial and yeast origins of replication, a bacterial bla resistance marker, the
Results
The neurabin gene was disrupted in embryonic stem cells using a replacement targeting vector that results in deletion of the first coding exon, producing a null allele. Western blot analysis of total brain homogenate using an antibody raised against the neurabin C-terminus (Muly et al., 2004a) confirmed a complete loss of neurabin protein expression (Fig. 1). Examination of PP1 levels in striatal extracts revealed a significant reduction (∼30%) in expression level in both neurabin KO mice and
Discussion
We have tested the requirement for the structurally similar synaptic scaffolding proteins, spinophilin and neurabin, in dopamine-mediated neuromodulation in KO mouse strains. We found altered responses in all paradigms examined, and the two strains differed strikingly in a number of ways. However, in both spinophilin and neurabin KO mice, striatal levels of PP1 were reduced, which is consistent with the proposed functional roles of these scaffolds in PP1 control. Presumably, a cellular
Acknowledgments
This research was supported by fellowships from NARSAD and the Tourette Syndrome Association (PBA), National Institutes of Health grants MH40899 and DA1044 (P.G.), and EEC grant “SYNSCAFF” (P.C.).
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2021, Advances in PharmacologyCitation Excerpt :Initially presumed to involve phosphatases, various kinases have also been implicated in NMDAR-LTD, including PP-1 activation of GSK-3β by dephosphorylation of GSK3β itself and its upstream inhibitor, Akt (Szatmari et al., 2005). Targeting of PP-1 to its substrates necessary for LTD requires the scaffolding protein spinophilin, as peptides that prevent the PP-1-spinophilin interaction and examination of glutamatergic responses in spinophilin knockout mice reveal potentiation of glutamate receptor responses (Yan et al., 1999) and a failure to elicit NMDAR-LTD (Allen et al., 2006; Morishita et al., 2001). Spinophilin also interacts with Group I mGluRs in the hippocampus to regulate receptor trafficking and signaling involved in mGluR-mediated synaptic plasticity.
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Present address: Intra-Cellular Therapies, Inc., 3960 Broadway, New York, NY 10021, USA.