We can rationally explain the postsynaptic accumulation of α2βγ2

We can rationally explain the postsynaptic accumulation of α2βγ2 and α3βγ2 receptors. By contrast the postsynaptic clustering of α1βγ2 receptors can occur in the absence of gephyrin and therefore probably depends on alternative mechanisms. Disruption of Tyr phosphorylation in γ2Y365/7F knockin Sirolimus concentration mice results in selective upregulation of GABAARs in CA3 pyramidal cells but, so far unexplained, not in CA1 pyramidal

cells (Tretter et al., 2009). Phosphorylation of γ2S327 is established to modulate the diffusional dynamics of postsynaptic GABAARs (Muir et al., 2010), yet the functionally relevant interaction partner(s) for this effect remain unknown. Lastly, gephyrin exists in multiple splice variants (Paarmann et al., 2006) and is phosphorylated at multiple sites (Huttlin et al., 2010 and Tyagarajan et al., 2011), yet the functional relevance of different gephyrin isoforms and their posttranslational modifications remain largely unexplored. One attractive mechanism underlying postsynaptic differentiation involves gephyrin-mediated interaction of GABAARs with NL2, which accumulates at synapses through interaction with presynaptic neurexin. However, the loss of GABAARs and gephyrin from inhibitory

synapses of NL2 knockout mice is incomplete (Hoon et al., 2009 and Jedlicka et al., 2011), suggesting that additional thus-far-unidentified synaptic adhesion complexes Obeticholic Acid molecular weight exist that substitute for NL2 and contribute to accumulation of GABAARs and gephyrin at many synapses. Interestingly, a recently described transsynaptic interaction between presynaptic neurexins and postsynaptic GABAARs appears to inhibit rather than promote the function of GABAergic synapses (Zhang et al., 2010). This negative effect of neurexin on GABAergic transmission was preserved in NL2 KO neurons and also observed in GABAAR expressing heterologous cells exposed to soluble neurexin constructs, indicating that it does not involve competition between GABAARs and NL2 for interaction with neurexin. The relevance of this interaction for native synapses and trafficking of GABAARs remains to be explored. A complete

understanding of the role of GABAAR trafficking in GABAergic synaptic plasticity will require that these knowledge Isotretinoin gaps be filled. In addition, downstream consequences of altered GABAergic transmission on other signaling pathways will need to be explored. Ultimately, the function of these mechanisms will need to be explored at the level of neural network activity, behavior, and cognition, including in appropriate disease models. We thank Victoria Cavener and Pam Mitchell for critical comments on the manuscript. Research in the Luscher laboratory has been supported by Grants MH62391, MH60989, and RC1MH089111 from the National Institutes of Mental Health (NIMH) and grants from the Pennsylvania Department of Health using Tobacco Settlement Funds.

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