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

Abstract

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

Memantine Disrupts Motor Coordination through Anxiety-like Behavior in CD1 Mice

“…In our previous studies, we found that excitotoxic processes, characteristic of a SCA1 mouse model, can be mimicked by chronic optogenetic overactivation of Bergmann glia, which expresses channelrhodopsin-2 [11]. Using this model, we showed that memantine administration significantly attenuated loss of Purkinje cells and preserved normal Bergmann glia morphology [12]. These data indicate that memantine may have therapeutic potential in SCA1.…”

“…Memantine (Sigma-Aldrich, St. Louis, MO, USA, cat. No M9292) was added to drinking water at 0.5 mg/mL, as described previously [12]. On average, mice consumed daily ~5.8 ± 0.2 mL/30 g of mouse body weight (consistent with [13]).…”