Facilitation of hippocampal long-term potentiation by astrocytic Gq signaling is compromised in an advanced Alzheimer's disease model.

Astrocytes communicate bidirectionally with neurons by releasing various signaling molecules. This astrocyte-neuron "dialogue" is essential for long-term processes in the nervous system, and its disruption correlates with various neuropathologies, including Alzheimer's disease (AD). Neurogenetic approaches including opto- and chemogenetics allow targeted modulation of astrocyte functioning. Our study investigated how chemogenetic activation of the Gq-coupled pathway in hippocampal astrocytes modulates synaptic plasticity and gene expression in both healthy state and AD pathology. To selectively manipulate astrocytic Gq signaling, we expressed DREADD receptors hM3Dq in hippocampal astrocytes of both wild-type (WT) and transgenic 5xFAD mice, a model of familial Alzheimer's disease, using adeno-associated viruses. In the acute brain slices, we assessed the amplitude of field excitatory postsynaptic potentials (fEPSPs) and expression of immediate early genes following activation of DREADD receptors hM3Dq via application of specific agonist Compound-21 (C21), both under resting conditions and during the induction of long-term potentiation (LTP) via theta-burst stimulation (TBS). High concentrations of C21 (2-10 µM) non-specifically increased fEPSPs amplitude even in slices lacking DREADD expression, indicating significant off-target effects. At a lower concentration (1 µM), C21 did not alter baseline synaptic transmission in mice of both genotypes. In healthy animals, chemogenetic astrocyte stimulation with C21 (1 µM) can robustly enhance activity-dependent plasticity without altering the transcription of immediate early genes. In contrast, in 5xFAD slices, the fEPSPs amplitudes were already potentiated following TBS stimulation. On this background, chemogenetic astrocyte stimulation with C21 (1 µM) elicited no further increase in LTP. Our work highlights a common pitfall in chemogenetic studies by demonstrating that excessive DREADD agonist concentrations (more than 1 µM) produce significant off-target effects. We further show that stimulation of astrocytic Gq signaling with low agonist concentration exerts a facilitation of long-term hippocampal plasticity in slices from healthy animals. However, the efficacy of targeted astrocytic Gq-mediated modulation appears limited in advanced-stage AD. LTP was enhanced and C21 did not facilitate it further, likely due to a significant reorganization of neuroglial communications.