Neurotransmitter Receptor Interactions Control Astrocyte Ca²⁺ Signal in the Basolateral Amygdala

The endocannabinoid (eCB) system plays fundamental roles in both physiological and pathological aspects of brain function. Activation of type 1 cannabinoid (CB1) receptors in astrocytes by eCBs elevates their intracellular calcium through a signaling pathway that involves activation of Gq/11 proteins, phospholipase C, and IP3R2 to mobilize calcium. Hippocampal astrocytes have been proposed to integrate synaptic information through nonlinear interactions between glutamate and acetylcholine in eliciting calcium responses. However, whether similar integrative interactions occur among other neurotransmitter receptors, namely CB1, glutamate, GABA, and dopamine, and in other brain regions remains unknown.

Here, we investigated whether CB1 receptor activation in astrocytes interacts with signaling pathways of other neurotransmitter receptor systems known to be coupled to Gq/11, Gs, and Gi/o proteins. We monitored astrocytic calcium dynamics in the basolateral amygdala (BLA), a region with prominent integrative functions across multiple neurotransmitter systems, in response to independent or simultaneous receptor activation.

We found that simultaneous activation of CB1 receptors with glutamate (Glu), dopamine, or GABA receptors elicited calcium signals that were significantly smaller than the linear summation of responses evoked by each receptor alone. This attenuation was observed in both astrocytic arborizations and somas and was independent of the distance of the domain from the soma. In contrast, the simultaneous activation of Glu and GABA receptors produced calcium responses comparable to the linear sum of their individual effects.

Our results extend the current understanding of endocannabinoid signaling by revealing that astrocytic CB1 receptor activation can dynamically interact with other neurotransmitter system receptors to generate nonlinear astrocyte calcium signaling outcomes in BLA astrocytes. The integrative signaling capabilities of astrocytes may be particularly relevant in the BLA, suggesting that astrocytes participate directly in shaping amygdala circuit function.

Together, these findings demonstrate that neurotransmitter-evoked calcium signaling in BLA astrocytes exhibits receptor-specific nonlinear interactions, supporting a role for astrocytes as integrative elements within local neural circuits.