Optogenetic Glia Manipulation: Possibilities and Future Prospects

Abstract

Our brains are composed of two distinct cell types: neurons and glia. Emerging data from recent investigations show that glial cells, especially astrocytes and microglia, are able to regulate synaptic transmission and thus brain information processing. This suggests that, not only neuronal activity, but communication between neurons and glia also plays a key role in brain function. Thus, it is currently well known that the physiology and pathophysiology of brain function can only be completely understood by considering the interplay between neurons and glia. However, it has not yet been possible to dissect glial cell type-specific roles in higher brain functions in vivo. Meanwhile, the recent development of optogenetics techniques has allowed investigators to manipulate neural activity with unprecedented temporal and spatial precision. Recently, a series of studies suggested the possibility of applying this cutting-edge technique to manipulate glial cell activity. This review briefly discusses the feasibility of optogenetic glia manipulation, which may provide a technical innovation in elucidating the in vivo role of glial cells in complex higher brain functions.

Keywords: Astrocyte; Higher brain functions; Microglia; Optogenetics; Synapse.

Fig. 1. A Schematic representation of a tripartite synapse. The tripartite synapse is composed of presynaptic and postsynaptic terminals with astrocytic processes enwrapping the synapses. The release of neurotransmitter from the presynaptic terminal acts on the postsynaptic terminal as well as with astrocytic receptors mediating intracellular Ca²⁺ elevation via Gq GPCR. Ca²⁺ elevation then triggers the release of gliotransmitters that react with the presynaptic and postsynaptic terminal receptors to modulate synaptic transmission.

Fig. 2. A diagrammatic research scheme to dissect in vivo function of glia in higher brain function using optogenetics. This scheme shows glial cell type-specific opsin gene expression by using viral vectors or cell type-specific transgenic mice (a). Upon optogenetic glia activation/inhibition (b), the in vivo glia function can be assessed by subjecting the mice in a series of behavioral tests (c). The function of glia in anxiety can be measured by elevated plus maze that is based on the aversion of mice to open spaces. The forced swimming test is the most frequently used behavioral test for assessing depression-related behaviors. To assess the recognition and aversive memory, behavioral tests such as novel object recognition and fear conditioning task can be used.