title: Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum.
abstract: Previous studies indicate that while transgenic mice with ATXN1[30Q]-D776-induced disease share pathological features caused by ATXN1[82Q] having an expanded polyglutamine tract, they fail to manifest the age-related progressive neurodegeneration seen in spinocerebellar ataxia type 1. The shared features include morphological alterations in climbing fiber (CF) innervation of Purkinje cells (PCs). To further investigate the ability of ataxin-1 (ATXN1) to impact CF/PC innervation, this study used morphological and functional approaches to examine CF/PC innervation during postnatal development in ATXN1[30Q]-D776 and ATXN1[82Q] cerebella. Notably, ATXN1[30Q]-D776 induced morphological alterations consistent with the development of the innervation of PCs by CFs being compromised, including a reduction of CF translocation along the PC dendritic tree, and decreased pruning of CF terminals from the PC soma. As previously shown for ATXN1[82Q], ATXN1[30Q]-D776 must enter the nucleus of PCs to induce these alterations. Experiments using conditional ATXN1[30Q]-D776 mice demonstrate that both the levels and specific timing of mutant ATXN1 expression are critical for alteration of the CF-PC synapse. Together these observations suggest that ATXN1, expressed exclusively in PCs, alters expression of a gene(s) in the postsynaptic PC that are critical for its innervation by CFs. To investigate whether ATXN1[30Q]-D776 curbs the progressive disease in ATXN1[82Q]-S776 mice, we crossed ATXN1[30Q]-D776 and ATXN1[82Q]-S776 mice and found that double transgenic mice developed progressive PC atrophy. Thus, the results also show that to develop progressive cerebellar degeneration requires expressing ATXN1 with an expanded polyglutamine tract.
authors.affiliation: Institute of Translational Neuroscience, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Ebner
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Ingram
authors.forename: Justin A
authors.initials: JA
authors.lastname: Barnes
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Duvick
authors.forename: Jill L
authors.initials: JL
authors.lastname: Frisch
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ebner
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000067696:Ataxin-1; D000067528:Ataxins; D064026:Calbindins; D002531:Cerebellum / Q000254:growth & development* / Q000473:pathology*; D004185:Disability Evaluation; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005456:Fluorescent Dyes; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D061848:Optical Imaging; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology*; D013569:Synapses / Q000235:genetics / Q000473:pathology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D064026:Calbindins; D005456:Fluorescent Dyes; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C104971:Pcp2 protein, mouse; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; D050599:Vesicular Glutamate Transport Protein 2; D049452:Green Fluorescent Proteins
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