Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice

Huntington's disease is an autosomal dominant disease which presents with s triatal and cortical degeneration causing involuntary movements, dementia a nd emotional changes. We employed 18-week-old transgenic Huntington mice (R 6/1 line developed by Bates and coworkers) that express exon 1 of the mutan t human Huntington gene with 115 CAG triplet repeats, At this age, R6/1 mic e do not exhibit an overt neurological phenotype nor any striatal neuronal loss. Using microdialysis, we monitored basal and intrastriatal N-methyl D- aspartate (NMDA, 100 muM, 15 min)- and KCI (100 mM, 15 min)-induced increas es in local aspartate, glutamate and GABA release in halothane-anaesthetize d transgenic mice and wild-type controls. Basal striatal dialysate glutamat e levels were reduced by 42% in R6/1 mice whilst aspartate and GABA levels did not differ from those observed in control mice. Intrastriatal NMDA was associated with significantly greater aspartate (at 15 min) and GABA (at 30 min) levels in the R6/1 mice compared to controls, whilst glutamate releas e rapidly increased to the same extent in both groups, Intrastriatal KCI wa s associated with enhanced increases (30 min) in local aspartate and glutam ate release in the R6/1 mice above those observed in controls whilst the ra pid increase (15 min) in GABA release was similar in both groups, The resul ts provide compelling evidence for specific alterations in both basal, as w ell as NMDA- and KCl-induced, release of striatal amino acid neurotransmitt ers in this transgenic model of Huntington's disease, even in the absence o f manifest neurodegeneration.