The expanding catalog of glutamate receptor auxiliary subuni

The expanding catalog of glutamate receptor auxiliary subunits and associated transmembrane proteins underscores the importance and complexity of the receptor complexes. Whereas the interactions described here specifically control AMPARs, distinct auxiliary subunits, Neto-1/2, modulate neuronal kainate receptors (Tomita and Castillo, 2012). The evolutionary conservation of these interacting proteins emphasizes that they serve fundamental roles (Wang et al., 2008). In C. elegans, the mixed AMPA/kainate receptor GLR-1 associates with STG (TARP-like), CNI (CNIH-2-like), and SOL (NETO-like). Elegant genetic studies in C. elegans have defined how these subunits globally regulate glutamate receptor number and function at worm synapses (Brockie et al., 2013). Analogous studies of the larger mammalian AMPAR complex represent a major challenge. Selective enrichment of PORCN in principal Homoharringtonine in hippocampus fits with its role in controlling incorporation of γ-8, which also has highest expression in these neurons. Similarly, CNIH-2 is concentrated in hippocampal neurons, where it specifically controls γ-8-containing AMPAR complexes (Herring et al., 2013; Kato et al., 2010). As hippocampal neurons play especially important roles in spatial navigation and memory consolidation, they may require multiple and complex mechanisms for controlling AMPAR trafficking and gating. Defining how this molecular ensemble orchestrates development and plasticity of hippocampal synapses will provide insights for understanding memory formation and how it goes awry in neuropsychiatric disorders.
Experimental Procedures
Author Contributions
Acknowledgments This work is partially supported by NIH/NIMH MH085080 (S.T.) and NIH/NINDS NS065920 (J.I.W.). We thank the McMahon lab (UAB) for help and advice with the plasticity experiments. We thank Dr. Ignatia B. Van den Veyver (Baylor College of Medicine), Dr. Kevin R. Jones (University of Colorado-Boulder), and Jackson Laboratory for generating and maintaining conditional PORCN and Emx1(Cre) mice. Requests for PORCN KO mice should be addressed to [email protected]
Introduction Long-term depression (LTD) of neurotransmission at multiple synapses is mediated by the endocytosis of synaptic AMPARs (Carroll et al., 2001, Malenka, 2003, Shepherd and Huganir, 2007, Snyder et al., 2001, Xiao et al., 2001). Regulated AMPAR internalization and the resulting synaptic depression can be triggered by diverse stimuli even within a single neuron type (Bear and Abraham, 1996, Massey and Bashir, 2007, Shepherd and Huganir, 2007). In CA1 hippocampal pyramidal neurons, activation of both N-Methyl-d-aspartic acid-type glutamate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs) trigger AMPAR internalization (Beattie et al., 2000, Daw et al., 2000, Kim et al., 2001, Man et al., 2000, Nosyreva and Huber, 2005, Snyder et al., 2001). Surprisingly, an early study found that NMDAR and mGluR-mediated LTD in CA1 hippocampal neurons did not occlude each other (Oliet et al., 1997). While this is normally indicative of independent expression mechanisms, the similar coupling of these pathways to AMPAR endocytosis raises a question as to how these two forms of depression may remain functionally independent. One explanation yet to be examined is if these LTD pathways actually mediate the internalization of different populations of AMPARs. A number of factors distinguish the induction mechanisms of NMDAR and mGluR mediated LTD. While NMDARs couple to receptor endocytosis through activation of phosphatases (PP1, PP2B) (Mulkey et al., 1993, Mulkey et al., 1994), mGluR signaling couples through a cascade requiring tyrosine phosphatases MAPK, and PI3K-Akt-mTOR signaling (Gallagher et al., 2004, Hou and Klann, 2004, Huang and Hsu, 2006, Huang et al., 2004, Moult et al., 2006). It has been recently shown that NMDAR-, but not mGluR-dependent LTD, and AMPAR endocytosis is blocked in the presence of an inhibitor of protein phosphatase 2A (PP2A) (Nicholls et al., 2008). Additionally, protein synthesis dependent mGluR-LTD, but not NMDAR-mediated LTD, was found to require Arc/Arg 3.1 translation leading to enhanced AMPAR endocytosis (Park et al., 2008, Waung et al., 2008). Such discrepancies seem to be indicative of the diversity in the processes coupled to AMPAR endocytosis; however, they do not provide evidence of whether these pathways ultimately converge on the internalization of a common population of synaptic AMPARs in hippocampal neurons.