Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice

Abstract

Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified PLCη remains largely unknown. We found that PLCη1 is prominently expressed in lateral habenula (LHb) astrocytes. Here, to investigate its physiological role, we generated astrocyte-specific PLCη1 conditional knockout (cKO) mice (Plch1f/f; Aldh1l1-CreERT2). In these cKO mice, we observed a reduction in cellular morphological complexity metrics, such as total process length, as well as a decrease in the passive membrane conductance of LHb astrocytes. Additionally, neuronal function was impacted by the cKO, as the synaptic efficacy and firing rates of LHb neurons increased, while extrasynaptic long-term depression was impaired. Both tonic α-amino-3-hydroxy-5-methyl-4-isoxazolepdlropionic acid receptor/N-methyl-d-aspartate receptor (AMPAR/NMDAR) currents and extracellular glutamate levels were reduced. Interestingly, chemogenetic activation of astrocytes restored the reduced tonic AMPAR/NMDAR currents in cKO mice. Furthermore, LHb astrocyte-specific deletion of PLCη1 via AAV-GFAP-Cre injection induced depressive-like behaviors in mice, which were reversed by chemogenetic activation of LHb astrocytes. Finally, we found that restraint stress exposure decreased Plch1 mRNA expression in the LHb. These findings suggest that PLCη1 could be a potential therapeutic target for depression and highlight the critical role of astrocytes in the etiology of neuropsychiatric disorders. © The Author(s) 2025.