Presence of Astrocytic S1R/5-HT1A Heterocomplex in the mPFC: A Putative Link to S1R Activation Mediated Faster...

In the brain, sigma non-opioid intracellular receptor 1/serotonin 1A receptor (S1R/5-HT1A) heterocomplexes are primarily localized within neuronal networks and play a key role in mediating the faster antidepressant-like effects induced by S1R activation. Existing evidence further suggests that astrocytes in medial prefrontal cortex (mPFC) contribute to these S1R-triggered, accelerated antidepressant responses. To address this, the current study employed neurochemical and in vivo fiber photometry approaches to examine whether S1R/5-HT1A heterocomplexes exist in astrocytes and modulate astrocytic structure and function, and their potential behavioral consequences. Behavioral analyses demonstrated that combined administration of S1R agonist SA4503 (1.0 mg/kg, i.p.) and 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, i.p.) elicited faster antidepressant-like responses, whereas 8-OH-DPAT alone at the tested dosage lacked intrinsic antidepressant activity. Utilizing in situ proximity ligation assay integrated with immunohistochemical labeling for astrocytic markers, S1R/5-HT1A heterocomplexes were identified within astrocytes of the hippocampus and mPFC. Subacute treatment with either SA-4503 alone or in combination with 8-OH-DPAT resulted in a significant elevation of these heterocomplexes in GFAP/S100β-positive cells, alongside an increase in astrocytic density, particularly within the mPFC. Pharmacological interventions further revealed that co-activation of S1R and 5-HT1A induced an enhanced astrocytic Ca²⁺ signaling, potentially counteracting the 5-HT1A-mediated suppression of astrocytic activity. Additionally, targeted knockdown of astrocytic S1R disrupted S1R/5-HT1A heterocomplex formation in the mPFC and induced a depressive-like phenotype in mice. These findings confirm the existence of astrocytic S1R/5-HT1A heterocomplexes in the mPFC and implicate this glial mechanism in the faster antidepressant effects facilitated by S1R activation.