Catecholamine exocytosis is diminished in R6/2 Huntington's disease model mice.
In this work, the mechanisms responsible for dopamine (DA) release impairments observed previously in Huntington's disease model R6/2 mice were evaluated. Voltammetrically measured DA release evoked in striatal brain slices from 12-week old R6/2 mice by a single electrical stimulus pulse was only 19% of wild-type (WT) control mice. Iontophoresis experiments suggest that the concentration of released DA is not diluted by a larger striatal extracellular volume arising from brain atrophy, but, rather, that striatal dopaminergic terminals have a decreased capacity for DA release. This decreased capacity was not due to an altered requirement for extracellular Ca(2+), and, as in WT mice, the release in R6/2 mice required functioning vesicular transporters. Catecholamine secretion from individual vesicles was measured during exocytosis from adrenal chromaffin cells harvested from R6/2 and WT mice. While the number of exocytotic events was unchanged, the amounts released per vesicle were significantly diminished in R6/2 mice, indicating that vesicular catecholamines are present in decreased amounts. Treatment of chromaffin cells with 3-nitropropionic acid decreased the vesicular release amount from WT cells by 50%, mimicking the release observed from untreated R6/2 cells. Thus, catecholamine release from tissues isolated from R6/2 mice is diminished because of impaired vesicle loading.
Johnson
Michael A
MA
Department of Chemistry The University of North Carolina, Chapel Hill, North Carolina, USA.
Villanueva
Melissa
M
Haynes
Christy L
CL
Seipel
Andrew T
AT
Buhler
Leah A
LA
Wightman
R Mark
RM
D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics / Q000502:physiology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007478:Iontophoresis / Q000295:instrumentation / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009574:Nitro Compounds / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics; D011422:Propionates / Q000494:pharmacology
D002395:Catecholamines; D003292:Convulsants; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D009687:Nuclear Proteins; D011422:Propionates; C015392:3-nitropropionic acid; D004298:Dopamine