Spectrum of BDNF expression changes and reactive glial phenotypes across brain regions precede neuronal loss and predict therapeutic effects of BDNF in early stages of SCA1 Abbreviated title: Brain wide SCA1 pathology and effects of BDNF

319 words) Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, and premature lethality. Due to the severe cerebellar degeneration seen in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contributes to the symptoms of SCA1. Here, using immunohistochemistry and gene expression analysis we investigated early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant SCA1 brain regions including the cerebellum, medulla oblongata, hippocampus, and motor cortex of Atxn1 mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 broadly. Our results indicate a spectrum of astrocyte and microglial phenotypes across brain regions early in SCA1. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1 in 12 week old Atxn1 mice, all of which are key for neuronal function, in the hippocampus and medulla. At the same age, the expression of these genes was increased in the cortex, indicating region-specific astrocyte reactive phenotypes. We have found altered microglial density throughout the brain, with decreases in cerebellar white matter but increases in medulla, motor cortex and corpus callosum. On the other hand, neuronal pathology was evident only in cerebellar Purkinje cells at this early stage of SCA1. We have previously shown that expression of brain-derived neurotrophic factor (BDNF), an astrocyte-released growth factor important for the survival and function of neurons, is reduced in the cerebellum, and exogenous BDNF treatment has therapeutic potential for cerebellar aspects of disease in Purkinje cells specific transgenic mouse model of SCA1 (Pcp2-ATXN1[82Q] line). We report here that BDNF expression is decreased in the cerebellar Bergmann glia of patients with SCA1. Moreover, we found brain region specific changes in BDNF expression in Atxn1 mice with decreased expression in the cerebellum and hippocampus, and increased expression in the medulla and cortex. Using ALZET pumps to deliver BDNF, we have found that BDNF treatment ameliorated several aspects of SCA1 pathogenesis, including motor deficits, learning and problem-solving strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus.