Serotonin Strengthens a Developing Glutamatergic Synapse through a PI3K-Dependent Mechanism

• Published in: The Journal of neuroscience 2024-02, Vol.44 (6), p.e1260232023
• Main Authors: Udoh, Uwemedimo G, Bruno, John R, Osborn, Paige O, Pratt, Kara G
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Circuits; Developmental stages; Down-regulation; Glutamatergic transmission; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Juveniles; N-Methyl-D-aspartic acid receptors; Neuromodulation; Neurons - physiology; Phosphatidylinositol 3-Kinases; Receptors; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Retina; Serotonin; Serotonin S2 receptors; Superior colliculus; Synapses; Synapses - physiology; Synaptic transmission; Synaptic Transmission - physiology; Synaptogenesis; Up-regulation; Vertebrates; Xenopus; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.1260-23.2023

It is well established that, during neural circuit development, glutamatergic synapses become strengthened via NMDA receptor (NMDAR)-dependent upregulation of AMPA receptor (AMPAR)-mediated currents. In addition, however, it is known that the neuromodulator serotonin is present throughout most regions of the vertebrate brain while synapses are forming and being shaped by activity-dependent processes. This suggests that serotonin may modulate or contribute to these processes. Here, we investigate the role of serotonin in the developing retinotectal projection of the tadpole. We altered endogenous serotonin transmission in stage 48/49 (∼10-21 days postfertilization) tadpoles and then carried out a set of whole-cell electrophysiological recordings from tectal neurons to assess retinotectal synaptic transmission. Because tadpole sex is indeterminate at these early stages of development, experimental groups were composed of randomly chosen tadpoles. We found that pharmacologically enhancing and reducing serotonin transmission for 24 h up- and downregulates, respectively, AMPAR-mediated currents at individual retinotectal synapses. Inhibiting 5-HT receptors also significantly weakened AMPAR-mediated currents and abolished the synapse strengthening effect seen with enhanced serotonin transmission, indicating a 5-HT receptor-dependent effect. We also determine that the serotonin-dependent upregulation of synaptic AMPAR currents was mediated via an NMDAR-independent, PI3K-dependent mechanism. Altogether, these findings indicate that serotonin regulates AMPAR currents at developing synapses independent of NMDA transmission, which may explain its role as an enabler of activity-dependent plasticity.