Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer’s Disease Mice Model

Abstract

Alzheimer’s disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aβ amyloid clearance from the brain. However, some recent evidence suggests that astrocytes may play a significant role in the pathogenesis of AD. In this paper, we evaluated the effects of the optogenetic activation of Gq-coupled exogenous receptors expressed in astrocytes as a possible way of restoring brain function in the AD mouse model. We evaluated the effects of the optogenetic activation of astrocytes on long-term potentiation, spinal morphology and behavioral readouts in 5xFAD mouse model of AD. We determined that in vivo chronic activation of astrocytes resulted in the preservation of spine density, increased mushroom spine survival, and improved performance in cognitive behavioral tests. Furthermore, chronic optogenetic stimulation of astrocytes resulted in the elevation of EAAT-2 glutamate uptake transporter expression, which could be a possible explanation for the observed in vivo neuroprotective effects. The obtained results suggest that the persistent activation of astrocytes may be considered a potential therapeutic approach for the treatment of AD and possibly other neurodegenerative disorders.

Optoα1AR activation in astrocytes modulates basal hippocampal synaptic excitation and inhibition in a stimulation‐specific manner

“…The use of OptoXRs (Airan et al, 2009) in astrocytes has emerged as another potential solution. Stimulation of Optoα1 adrenergic receptor (Optoα1AR)‐derived constructs can drive Ca 2+ elevations in cultured astrocytes (Figueiredo et al, 2014), alter neuronal activity both in vivo (Iwai et al, 2021) and in brain slices (Gerasimov et al, 2021), and stimulate memory enhancement in vivo (Adamsky et al, 2018; Gerasimov et al, 2023; Iwai et al, 2021). However, electrophysiological and behavioral responses using these tools have been inconsistent across studies, and results using optogenetic constructs in astrocytes appear highly sensitive to both brain region and optical stimulation paradigm.…”