The aim of the work was to create a model of selective cerebellar astrogliosis (using nonspecific (chronic photoactivation of Bergmann glia, expressing ChR2– BGChR2) and specific (expression of mutant Ataxin 1) cerebellar astrocyte stimuli), to study the effect of astroglia on transsynaptic transmission of Purkinje cells (PC) in the early stages of disease, and estimate the effect of memantine to this process.
To simulate astrocyte-induced cerebellar neurodegeneration, 10μl AVV GFAP-ChR2-mKate2 (3,4×10^7units/ml) was injected into the cerebral cortex of ICR (CD1) mice and photostimulated with repeated light pulses (λ=480 nm, 20ms at 0,1 Hz, series of 1 min with 1 min rest for 4 days) by LED fixed above the injection area to the bones of the skull. Mice of the second experimental group were injected with 3 μl of LVV GFAP-ATXN1[Q85]-Flag (6,8×10^9units/ml). Control mice were injected with 10 μl PBS.
Material was collected from the affected brain regions. According to the results of IHC, in the model with chronic photoactivation of BGChR2 the number of PCs and the ML thickness decreased. Using the patch clamp we found that capacitance of PCs was also decreased in these animals.
To assess the neuroprotective effect in animals with reactive BGChR2 we used memantine solution (90 mg/kg body weight) within 4 days of photoactivation. Memantine decreased excitotoxicity through increase number of glutamate reuptake molecules, such as EAAT1. It leads to partial restoration of normal BGChR2 morphology. Also it positively affects PC dendritic tree and the total number of PСs. Thus, a decrease in excitotoxicity may be due to the direct effect of NMDA receptor blockers on astrocytes and indirectly on PC through increased glutamate reuptake, which protects against neurodegeneration.
We found similar pathomorphological changes and the positive effect of oral administration of memantine in an astrogliosis model with selective expression of mutant Ataxin 1 in BG.