title: α-Synuclein accumulation reduces GABAergic inhibitory transmission in a model of multiple system atrophy.
abstract: Multiple system atrophy is a neurodegenerative disease caused by abnormal α-synuclein (α-syn) accumulation in oligodendrocytes and neurons. We previously demonstrated that transgenic (Tg) mice that selectively overexpressed human α-syn in oligodendrocytes exhibited neuronal α-syn accumulation. Microtubule β-III tubulin binds to endogenous neuronal α-syn to form an insoluble complex, leading to progressive neuronal degeneration. α-Syn accumulation is increased in the presynaptic terminals of Tg mice neurons and may reduce neurotransmitter release. To clarify the mechanisms underlying its involvement in neuronal dysfunction, in the present study, we investigated the effects of neuronal α-syn accumulation on synaptic function in Tg mice. Using whole-cell patch-clamp recording, we found that the frequency of miniature inhibitory postsynaptic currents was reduced in Tg mice. Furthermore, a microtubule depolymerizing agent restored normal frequencies of miniature inhibitory postsynaptic currents in Tg mice. These findings suggest that α-syn and β-III tubulin protein complex plays roles for regulation of synaptic vesicle release in GABAergic interneurons, and it causes to reduce GABAergic inhibitory transmission.
authors.affiliation: Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 35 Gengo, Obu-shi, Aichi 474-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Chenghua
authors.initials: C
authors.lastname: Jin
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Ikuru
authors.initials: I
authors.lastname: Yazawa
mesh_terms: D000818:Animals; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000503:physiopathology*; D009435:Synaptic Transmission; D014404:Tubulin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D014404:Tubulin; D051844:alpha-Synuclein; C462941:beta3 tubulin, mouse