Memantine suppresses the excitotoxicity but fails to rescue the ataxic phenotype in SCA1 model mice.

Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.

Belozor OS ，Vasilev A ，Mileiko AG ，Mosina LD ，Mikhailov IG ，Ox DA ，Boitsova EB ，Shuvaev AN ，Teschemacher AG ，Kasparov S ，Shuvaev AN ... -  《-》

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

Shuvaev AN ，Belozor OS ，Mozhei OI ，Shuvaev AN ，Fritsler YV ，Khilazheva ED ，Mosyagina AI ，Hirai H ，Teschemacher AG ，Kasparov S ... -  《Cells》

Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1).

Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice.

Hamel K ，Moncada EL ，Sheeler C ，Rosa JG ，Gilliat S ，Zhang Y ，Cvetanovic M ... -  《-》

Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice.

Shuvaev AN ，Belozor OS ，Mozhei OI ，Khilazheva ED ，Shuvaev AN ，Fritsler YV ，Kasparov S ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1.

Luttik K ，Tejwani L ，Ju H ，Driessen T ，Smeets CJLM ，Edamakanti CR ，Khan A ，Yun J ，Opal P ，Lim J ... -  《-》