Molecular targets for optogenetic stimulation of astrocytes for recovering cognitive functions in neurological complications

Abstract

Recently, mounting evidence suggests that cognitive impairment may accompany traditional neurological diseases, such as neurodegenerative disorders, as well as result from previous infections (COVID-19, influenza). One approach to mitigating the neurological pathological state involves regulating abnormal neural activity. Nevertheless, addressing this issue directly may not always be feasible due to neuronal overexcitation or inadequate stimulation, leading to unfavorable outcomes. Meanwhile, astrocytes adapt their activation levels exclusively to the group of neurons requiring activation, boosting cognitive functions as an example [1]. Optogenetics was employed in this study to selectively stimulate metabotropic astrocyte receptors in acute hippocampal slices of mice with an Alzheimer’s model. The aim was to examine the effect on electrophysiological function of neurons, strength of synaptic contacts ex vivo, and cognitive performance in vivo. Several fundamentally different approaches exist for optogenetic stimulation of cells, including the use of molecular targets such as ionotropic receptors (e.g., ChR2) or metabotropic receptors (e.g., OptoGq). Our studies have shown enhanced activity of hippocampal pyramidal neurons and potentiated field excitatory potentials (fEPSP) following optogenetic activation of astrocytes expressing the metabotropic construct OptoGq. Conversely, the use of ChR2 resulted in an opposite effect [2]. For this reason, all subsequent investigations used a metabotropic construct. Astrocytes are known to respond to external stimuli via intracellular calcium [Ca2+] waves. The propagation of this wave results in the release of D-serine, cytokines, and lactate, subsequently modulating the activity of neurons. The role of astrocytes in regulating the function of NMDA receptors by releasing or removing glutamate from the extracellular environment is critical in modulating neural network excitation. Given the association of astrocytes with the pathogenesis and pathological mechanisms involved in neurodegenerative disorders, controlling their activity becomes a pressing and indispensable aspect of therapy. In the present investigation, optogenetic stimulation of hippocampal astrocytes transduced by AAV5_GfaABC1D_opto-a1AR-EYFP virus (which encodes a Gq-coupled metabotropic receptor) resulted in enhanced electrophysiological activity of hippocampal pyramidal neurons. This was evidenced by increased sEPSC of pyramidal neurons and the potentiation of field excitatory postsynaptic potentials (fEPSP) in the hippocampal region, following light activation of astrocytes [2]. A significant activation of early gene expression (cRel, Arc, Fos, JunB, and Egr1) was detected in hippocampal slices [3]. Additionally, optogenetic activation of the metabotropic receptor during behavioral tests in vivo restored cognitive functions in mice with an Alzheimer’s disease model. The activation of the Gq-coupled metabotropic receptor was found to be a molecular target that promotes positive changes in neuronal functioning at ex vivo and in vivo levels in both wild type mice and a mouse model of Alzheimer’s disease. Expression of OPTO-α1AR in astrocytes could potentially have a beneficial impact on other neuropathological conditions. In the future, alternative less-invasive methods, such as chemogenetics, could be employed to specifically activate astrocytes in distinct brain regions.