title: Reduced striatal acetylcholine efflux in the R6/2 mouse model of Huntington's disease: an examination of the role of altered inhibitory and excitatory mechanisms.
abstract: Huntington's disease (HD) is a genetic neurodegenerative disorder that is characterized by the progressive onset of cognitive, psychiatric, and motor symptoms. In parallel, the neuropathology of HD is characterized by progressive loss of projection neurons in cortex and striatum; striatal cholinergic interneurons are relatively spared. Nonetheless, there is evidence that striatal acetylcholine (ACh) function is altered in HD. The present study is the first to examine striatal ACh function in awake, behaving animals, using the R6/2 mouse model of HD, which is transgenic for exon 1 of the mutant huntingtin gene. Physiological levels of extracellular striatal ACh were monitored in R6/2 mice and wild type controls using in vivo microdialysis. Results indicate that spontaneous ACh release is reduced in R6/2 mice relative to controls. Intrastriatal application of the GABA(A) antagonist bicuculline methiodide (10.0 μM) significantly elevated ACh levels in both R6/2 mice and wild type controls, while overall ACh levels were reduced in the R6/2 mice compared to the wild type group. In contrast, systemic administration of the D(1) dopamine receptor partial agonist, SKF-38393 (10.0mg/kg, IP), elevated ACh levels in control animals, but not R6/2 mice. Taken together, the present results suggest that GABA-mediated inhibition of striatal ACh release is intact in R6/2 mice, further demonstrating that cholinergic interneurons are capable of increased ACh release, whereas D(1) receptor-dependent activation of excitatory inputs to striatal cholinergic interneurons is dysfunctional in R6/2 mice. Reduced levels of extracellular striatal ACh in HD may reflect abnormalities in the excitatory innervation of cholinergic interneurons, which may have implications ACh-dependent processes that are altered in HD, including corticostriatal plasticity.
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ 07102, USA. afarrar@andromeda.rutgers.edu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Farrar
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Callahan
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Abercrombie
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D059329:Cholinergic Neurons / Q000473:pathology / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018491:Dopamine Agonists; D058787:GABA-A Receptor Antagonists; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000109:Acetylcholine; D004298:Dopamine; D001640:Bicuculline