Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodeling of both postsynaptic density and NMDA receptor signaling.
We study the striatal susceptibility to NMDA receptor (NMDAR)-mediated injury of two Huntington's disease (HD) transgenic mice: R6/1 and R6/1:BDNF(+/-). We found that R6/1:BDNF(+/-) mice--which express reduced levels of BDNF--were more resistant than R6/1 mice to intrastriatal injection of quinolinate. This increased resistance is related to a differential reduction in expression of NMDAR scaffolding proteins, MAGUKs (PSD-95, PSD-93, SAP-102 and SAP-97) but not to altered levels or synaptic location of NMDAR. A robust reorganization of postsynaptic density (PSD) was detected in HD transgenic mice, shown by a switch of PSD-93 by PSD-95 in PSD. Furthermore, NMDAR signaling pathways were affected by different BDNF levels in HD mice; we found a reduction of synaptic alpha CaMKII (but not of nNOS) in R6/1:BDNF(+/-) compared to R6/1 mice. The specific regulation of MAGUKs and alpha CaMKII in striatal neurons may reflect a protective mechanism against expression of mutant huntingtin exon-1.
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Jesús F
JF
Torres-Peraza
Albert
A
Giralt
Juan M
JM
García-Martínez
Edurne
E
Pedrosa
Josep M
JM
Canals
Jordi
J
Alberch
D000328:Adult; D000368:Aged; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000235:genetics*
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins