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It is well established that, during neural circuit development, glutamatergic synapses become strengthened via NMDA receptor (NMDAR)-dependent up-regulation 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 Xenopus tadpole. We altered endogenous serotonin transmission in stage 48/49 (approximately 10-21 days postfertilization) Xenopus 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 comprised of randomly chosen tadpoles. We found that pharmacologically enhancing and reducing serotonin transmission for 24 hours up- and down-regulates, respectively, AMPAR-mediated currents at individual retinotectal synapses. Inhibiting 5HT-2 receptors also significantly weakened AMPAR-mediated currents and abolished the synapse strengthening effect seen with enhanced serotonin transmission, indicating a 5HT-2 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 synapse independent of NMDA transmission, which may explain its role as an enabler of activity-dependent plasticity.Significance Statement Glutamate is the main excitatory transmitter in the central nervous system, and so the formation of synapses to support robust glutamatergic transmission is important for healthy brain function. It is well established that, during development, activity-dependent, Hebbian-like plasticity strengthens and refines glutamatergic synapses. Here, we report that the neuromodulator serotonin also strengthens developing glutamatergic synapses. This strengthening occurs through an activity independent mechanism that involves the activation of phosphoinositide signaling. Overall, this study suggests that a combination of activity dependent and independent mechanisms strengthens glutamatergic synapses during development.
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