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 SCA1. The shared features include morphological alterations in climbing fiber (CF) innervation of Purkinje cells (PCs). To further investigate the ability of 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. Like 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 ATXN1expression 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.

Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1

“…To further examine the time-line of glial activation in response to transgene expression we performed immunofluorescence studies at three weeks, approximately one week after ATXN1 expression starts in ATXN1[82Q] mice (Ebner et al, 2013). We detected a statistically higher GFAP levels even at this early age that continued to increase with disease progression ( Figure 3e , 115% of wild-type levels, n = 3 pairs, p= 0.0167 comparing 3 weeks old wild type and ATXN1[82Q] mice; P = 0.0013 comparing 3 weeks old to 8-12 weeks old ATXN1[82Q] mice).…”

“…Recently, a conditional transgenic line cATXN1[30Q]-D776 was generated where the expression of the phosphomimetic pathogenic ATXN1 —ATXN1 [30Q] D776— can be turned off by administering the tetracycline derivative doxycycline (DOX) (Ebner et al, 2013). In cATXN1 [30Q]-D776 mice where the transgene was expressed for the first 6 weeks of life and turned off for another 6 weeks, a full recovery of motor behavior—as evidenced by their ability to stay on the accelerating rotarod—was attained (Ingram, unpublished data).…”

“…The most intriguing of these models are the ATXN1 [82Q]-A776 line, where replacing this serine with an alanine residue prevents toxicity of expanded ATXN1 (Emamian et al, 2003); and the ATXN1 [30Q]-D776 line, where replacing the same serine residue with a phosphomimetic aspartate residue causes features of SCA1 to occur even in the absence of a pathogenic polyglutamine tract (Duvick et al, 2010; Emamian et al, 2003). Finally, there are excellent conditional SCA1 models where mutant ATXN1 is under the control of a doxycycline (DOX) responsive promoter that can be turned on or off at will, thus influencing the disease phenotype (Ebner et al, 2013). Using these mouse models, we demonstrate that glial pathology in SCA1 closely correlates with disease onset and severity and that it is induced by neuronal dysfunction and not neuronal death.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Abnormalities are first apparent at the onset of motor symptoms, when Purkinje neuron responsiveness to climbing fiber input is dramatically reduced [29]. At this stage, there are also abnormalities in the structure of climbing fiber synaptic contacts, namely a loss of synapses in the distal dendritic tree and persistence of climbing fiber contacts on the soma that are normally pruned during development [30]. With disease progression, Purkinje neurons continue to show reduced responsiveness at climbing fiber synapses and a reduction in the volume of climbing fiber afferents onto Purkinje neurons [31].…”

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…In both knockin and transgenic models of SCA1, defects in Purkinje cell (PC) synaptic connectivity precede ataxia (6)(7)(8), and gene expression changes appear within the first few weeks of life (8)(9)(10)(11)(12)(13). During this early period, neurogenesis is still taking place within a niche of postnatal stem cells in the cerebellar white matter, which led us to ask whether early neurodevelopment might go awry in ways that alter the neural circuitry of the cerebellum.…”