Serotonin receptor 4 regulates hippocampal astrocyte morphology and function

Astrocytes are an important component of the multipartite synapse and crucial for proper neuronal network function. Although small GTPases of the Rho family are powerful regulators of cellular morphology, the signaling modules of Rho‐mediated pathways in astrocytes remain enigmatic. Here we demonstrated that the serotonin receptor 4 (5‐HT4R) is expressed in hippocampal astrocytes, both in vitro and in vivo. Through fluorescence microscopy, we established that 5‐HT4R activation triggered RhoA activity via Gα13‐mediated signaling, which boosted filamentous actin assembly, leading to morphological changes in hippocampal astrocytes. We investigated the effects of these 5‐HT4R‐mediated changes in mixed cultures and in acute slices, in which 5‐HT4R was expressed exclusively in astrocytes. In both systems, 5‐HT4R‐RhoA signaling changed glutamatergic synaptic transmission: It increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in mixed cultures and reduced the paired‐pulse‐ratio (PPR) of field excitatory postsynaptic potentials (fEPSPs) in acute slices. Overall, our present findings demonstrate that astrocytic 5‐HT4R‐Gα13‐RhoA signaling is a previously unrecognized molecular pathway involved in the functional regulation of excitatory synaptic circuits. Main Points Astrocytes heterogeneously express 5‐HT4R in vivo and in vitro 5‐HT4R stimulation leads to Gα13–mediated RhoA activation, actin reorganization and morphological changes 5‐HT4R signaling in astrocytes modulates excitatory synapses