Bidirectional control of postsynaptic density-95 (PSD-95) clustering by huntingtin [Cell Biology]

December 17th, 2013 by Parsons, M. P., Kang, R., Buren, C., Dau, A., Southwell, A. L., Doty, C. N., Sanders, S. S., Hayden, M. R., Raymond, L. A.

Huntington Disease (HD) is associated with early alterations in cortical-striatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. While many of these synaptic alterations are thought to be attributable to a toxic gain-of-function of the mutant huntingtin (mHTT) protein, the role that non-pathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from wild-type (WT) mice and mice overexpressing HTT with 18 glutamine repeats (YAC18; non-pathogenic). We find that HTT overexpression increases PSD-95 palmitoylation in striatal but not cortical tissue and results in a palmitoylation-dependent increase in PSD-95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co-cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone is insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that non-pathogenic HTT can indeed influence synaptic protein localization and uncovers a novel role of Htt in PSD-95 distribution.