Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion of the polyglutamine tract in the ATXN1 gene and the subsequent buildup of mutant Ataxin-1 protein. In addition to its toxicity, mutant Ataxin-1 protein interferes with gene expression and signal transduction in cells. Recently, it is evident that ATXN1 is not only expressed in neurons but also in glia, however, it is unclear the extent to which either contributes to the overall pathology of SCA1. There are various ways to model SCA1 in mice. Here, functional deficits at cerebellar synapses were investigated in two mouse models of SCA1 in which mutant ATXN1 is either nonspecifically expressed in all cell types of the cerebellum (SCA1 knock-in (KI)), or specifically in Bergmann glia with lentiviral vectors expressing mutant ATXN1 under the control of the astrocyte-specific GFAP promoter. We report impairment of motor performance in both SCA1 models. In both cases, prominent signs of astrocytosis were found using immunohistochemistry. Electrophysiological experiments revealed alteration of presynaptic plasticity at synapses between parallel fibers and PCs, and climbing fibers and PCs in SCA1 KI mice, which is not observed in animals expressing mutant ATXN1 solely in Bergmann glia. In contrast, short- and long-term synaptic plasticity was affected in both SCA1 KI mice and glia-targeted SCA1 mice. Thus, non-neuronal mechanisms may underlie some aspects of SCA1 pathology in the cerebellum. By combining the outcomes of our current work with our previous data from the B05 SCA1 model, we further our understanding of the mechanisms of SCA1.

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1

“…Specifically, these alterations could affect intrinsic PN excitability, as well as alter synaptic responses. 14 , 59 , 60 , 61 Ataxin-1 controls the expression of Ca v 3.1 and TRPC3 channels, involved in the regulation of intrinsic PN excitability, and mutant Ataxin-1 renders PNs hyperexcitable in a cell-autonomous fashion. 30 Therefore, homeostatic mechanisms in response to excess MLIN-mediated inhibition might lead to further reductions in the expression of these receptors and anticipate PN degeneration.…”

3,5-Dimethyladamantan-1-amine Restores Short-term Synaptic Plasticity by Changing Function of Excitatory Amino Acid Transporters in Mouse Model of Spinocerebellar Ataxia Type 1

“…Changes in the cerebellar cortex caused by target expression of mutant ataxin-1 in the Bergmann glia were described in detail previously [23]. In this study, SCA1 mice were administered 0.35 mg/kg memantine for 9 weeks starting from postnatal day 21 to block neurodegenerative process.…”

“…We used SCA1 mouse model with LVV GFAP-ATXN1[Q85]-Flag target expression in the Bergmann glia [23] to assess the effects of memantine on the processes involved in short-term synaptic plasticity. Memantine was administered in drinking water for 9 weeks at 0.35 mg/kg.…”

The pathogenetic basis for a disease continuum in early- and late-onset ataxia-dystonia supports a unified genetic diagnostic approach

“…Disturbances of these processes may have different consequences depending on the underlying genetic defect and its effect at protein level [23]. For example, impaired synaptic signaling due to Purkinje cell degeneration may be related to pathogenetic variants in: 1) mitochondrial tRNA aminoacylation genes, such as RARS2, leading to EOA(D+) [35][36][37], or 2) transcriptional regulator genes, like ATNX1, leading to LOA(D+) [23,38,39]. Interestingly, biological processes related to cellular organization and nervous system development were enriched in all gene groups, possibly suggesting a common developmental origin for ataxia-dystonia.…”