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 G alpha(13)-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-G alpha(13)-RhoA signaling is a previously unrecognized molecular pathway involved in the functional regulation of excitatory synaptic circuits.

Automated summary

Recent research has shown that the serotonin receptor 4 (5-HT4R) is expressed in hippocampal astrocytes, where its activation triggers RhoA activity via G alpha(13)-mediated signaling, leading to morphological changes. This signaling pathway can alter glutamatergic synaptic transmission, affecting the functional regulation of neuronal networks.