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.
Highlights
(astrocytic staining/expression was strongly increased while anti-Calbindin (PCs marker) stainmarker) staining/expression was strongly increased while anti-Calbindin (PCs marker) ing/expression was greatly reduced compared to the animals, which were not photostimstaining/expression was greatly reduced compared to the animals, which were not photoulated (Figure 2A,B)
The aim of this work was to investigate whether memantine could be protective in a model of cerebellar neurodegeneration induced by chronic optogenetic activation of channelrhodopsin- 2 (ChR2) expressed in Bergmann Glia (BG) ([5] and Figure 1A–C)
The impact is selectively directed against model of cerebellar neurodegeneration induced by chronic optogenetic activation of ChR2 expressed in BG ([5] and Figure 1A–C)
Summary
Astrocytes, including BG, play a key role in glutamate uptake through excitatory amino acid transporter type 1 (EAAT1) [1]. Neurodegenerative diseases, such as spinocerebellar ataxias (SCA), evoke pathological transformation of BG, manifested by increased thickness and decreased length of its processes. This reactive phenotype compromises glutamate uptake from synapses between parallel fibers (PF) and Purkinje cells (PC) [2,3]. Glutamate hyperactivates synaptic and extrasynaptic NMDA receptors, leading to excessive
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