Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum.
In Huntington's disease (HD), neuronal loss is most prominent in the striatum leading to emotional, cognitive and progressive motor dysfunction. The R6/2 mice, transgenic for exon 1 of the HD gene, develop a neurological phenotype with similarities to these features of HD. In striatal tissue, electrically evoked release of tritiated acetylcholine (ACh) and dopamine (DA) were compared in wild-type (WT) and R6/2 mice. In R6/2 mice, the evoked release of ACh, its M2 autoreceptor-mediated maximum inhibition and its dopamine D2 heteroreceptor-mediated maximum inhibition was diminished to 51%, 74% and 87% of controls, respectively. Also, the activities of choline acetyltransferase and of synaptosomal high-affinity choline uptake decreased progressively with age in these mice. In the DA release model, however, electrical stimulation elicited equal amounts of [3H]-DA both in WT and R6/2 mice. Moreover, high-affinity DA uptake into striatal slices was similar in WT and R6/2 mice. In order to confirm these findings in vivo, intrastriatal levels of extracellular DA were measured by intracerebral microdialysis in freely moving mice: striatal DA levels were found to be equal in WT and R6/2 mice. In conclusion, in the transgenic R6/2 mice changes occur mainly in striatal cholinergic neurones and their pre-synaptic modulation, but not in the dopaminergic afferent terminals. Whether similar events also contribute to the pathogenesis of HD in humans has to be established.
Vetter
J M
JM
Section of Clinicial Neuropharmacology, Neurozentrum, Breisacherstrasse 64, D-79106 Freiburg, Germany. janvetter@gmx.de
Jehle
T
T
Heinemeyer
J
J
Franz
P
P
Behrens
P F
PF
Jackisch
R
R
Landwehrmeyer
G B
GB
Feuerstein
T J
TJ
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002794:Choline / Q000493:pharmacokinetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D004558:Electric Stimulation; D005091:Exons; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D018377:Neurotransmitter Agents / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism*; D043585:Receptor, Muscarinic M2; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D018377:Neurotransmitter Agents; D043585:Receptor, Muscarinic M2; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D013779:Tetrodotoxin; D002795:Choline O-Acetyltransferase; D002794:Choline; D000109:Acetylcholine; D002118:Calcium; D004298:Dopamine