Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodelling of both postsynaptic density and NMDA receptor signalling

Abstract

We study the striatal susceptibility to NMDA receptor (NMDAR)-</p><p>mediated injury of two Huntington’s disease (HD) transgenic mice:</p><p>R6/1 and R6/1:BDNF+/−. We found that R6/1:BDNF+/− mice – which</p><p>express reduced levels of BDNF – were more resistant than R6/1 mice</p><p>to intrastriatal injection of quinolinate. This increased resistance is</p><p>related to a differential reduction in expression of NMDAR scaffolding</p><p>proteins, MAGUKs (PSD-95, PSD-93, SAP-102 and SAP-97) but not</p><p>to altered levels or synaptic location of NMDAR. A robust reorganization</p><p>of postsynaptic density (PSD) was detected in HD transgenic</p><p>mice, shown by a switch of PSD-93 by PSD-95 in PSD. Furthermore,</p><p>NMDAR signaling pathways were affected by different BDNF levels in</p><p>HD mice; we found a reduction of synaptic αCaMKII (but not of</p><p>nNOS) in R6/1:BDNF+/− compared to R6/1 mice. The specific regulation</p><p>of MAGUKs and αCaMKII in striatal neurons may reflect a</p><p>protective mechanism against expression of mutant huntingtin exon-1.