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

Abstract

Astrocytes play active roles at synapses and can monitor, respond, and adapt to local synaptic activity. While there is abundant evidence that astrocytes modulate excitatory transmission in the hippocampus, evidence for astrocytic modulation of hippocampal synaptic inhibition remains more limited. Furthermore, to better investigate roles for astrocytes in modulating synaptic transmission, more tools that can selectively activate native G protein signaling pathways in astrocytes with both spatial and temporal precision are needed. Here, we utilized AAV8‐GFAP‐Optoα1AR‐eYFP (Optoα1AR), a viral vector that enables activation of Gq signaling in astrocytes via light‐sensitive α1‐adrenergic receptors. To determine if stimulating astrocytic Optoα1AR modulates hippocampal synaptic transmission, recordings were made in CA1 pyramidal cells with surrounding astrocytes expressing Optoα1AR, channelrhodopsin (ChR2), or GFP. Both high‐frequency (20 Hz, 45‐ms light pulses, 5 mW, 5 min) and low‐frequency (0.5 Hz, 1‐s pulses at increasing 1, 5, and 10 mW intensities, 90 s per intensity) blue light stimulation were tested. 20 Hz Optoα1AR stimulation increased both inhibitory and excitatory postsynaptic current (IPSC and EPSC) frequency, and the effect on miniature IPSCs (mIPSCs) was largely reversible within 20 min. However, low‐frequency stimulation of Optoα1AR did not modulate either IPSCs or EPSCs, suggesting that astrocytic Gq‐dependent modulation of basal synaptic transmission in the hippocampus is stimulation‐dependent. By contrast, low‐frequency stimulation of astrocytic ChR2 was effective in increasing both synaptic excitation and inhibition. Together, these data demonstrate that Optoα1AR activation in astrocytes changes basal GABAergic and glutamatergic transmission, but only following high‐frequency stimulation, highlighting the importance of temporal dynamics when using optical tools to manipulate astrocyte function.

Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice

“…Our study demonstrates impaired memory function following repeated optogenetic astrocyte stimulation via ChR2. This contrasts with the enhanced neuronal activity observed with Optoα1AR stimulation in a previous study [ 118 ]. Additionally, our study reveals reactive astrocyte induction via repeated optogenetic and chemogenetic stimulations—a phenomenon not observed with Optoα1AR stimulation [ 74 ].…”