Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre‐synaptic function in the striatum

• Published in: Journal of neurochemistry 2003-05, Vol.85 (4), p.1054-1063
• Main Authors: Vetter, J. M., Jehle, T., Heinemeyer, J., Franz, P., Behrens, P. F., Jackisch, R., Landwehrmeyer, G. B., Feuerstein, T. J.
• Format: Article
• Language: English
• Subjects: acetylcholine; Acetylcholine - metabolism; Animals; Biological and medical sciences; Calcium - metabolism; Choline - pharmacokinetics; Choline O-Acetyltransferase - metabolism; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; dopamine; Dopamine - metabolism; Dopamine - pharmacokinetics; Electric Stimulation; Exons; Extracellular Space - metabolism; Female; Humans; Huntington Disease - genetics; Huntington Disease - physiopathology; Huntington's disease; In Vitro Techniques; Male; Medical sciences; Mice; Mice, Transgenic; Microdialysis; Neurology; Neurotransmitter Agents - physiology; Presynaptic Terminals - metabolism; Receptor, Muscarinic M2; Receptors, Dopamine D2 - metabolism; Receptors, Muscarinic - metabolism; striatum; Tetrodotoxin - pharmacology; transgenic mice
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01704.x

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.