Sequential maturation of supramammillary glutamatergic/GABAergic co-transmission onto adult-born dentate granule cells
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Hypothalamic supramammillary nucleus (SuM) neurons project to the dentate gyrus and co-release glutamate and GABA, thereby regulating hippocampal information processing. However, how synapses mediating glutamate/GABA co-transmission are established during development remains unclear. Here, we investigated the functional and structural maturation of SuM inputs onto adult-born granule cells (GCs). We found that most newborn GCs received GABAergic responses without detectable glutamatergic responses, whereas a smaller population exhibited glutamate/GABA co-transmission. Newborn GCs with glutamate/GABA co-transmission showed more mature anatomical and physiological properties than GABA-only neurons, with greater dendritic complexity, longer dendritic length, lower input resistance, and stronger medial perforant path inputs. Postsynaptic depolarization failed to induce synapse unsilencing in GABA-only neurons but induced robust long-term potentiation in newborn GCs with glutamatergic transmission, indicating that plasticity at SuM inputs emerges after functional glutamatergic transmission is established. Morphological analysis showed that SuM terminals apposed to newborn GCs contained both VGluT2 and VIAAT, whereas postsynaptic receptor organization remained immature. Moreover, environmental enrichment and chemogenetic activation of SuM neurons increased the proportion of newborn GCs receiving glutamate/GABA co-transmission, suggesting that SuM activity promotes the emergence of glutamatergic transmission. Together, these results suggest that SuM inputs onto newborn GCs undergo sequential maturation from initial GABAergic transmission to glutamate/GABA co-transmission, a process likely supported by SuM activity-dependent postsynaptic maturation.
Significance
Synaptic transmission is generally thought to be mediated by a single neurotransmitter, yet some synapses use more than one neurotransmitter. How these dual-transmitter synapses are formed during neuronal development remains poorly understood. We studied inputs from the supramammillary nucleus to adult-born dentate granule cells, a model in which synapses mature as newborn neurons integrate into hippocampal circuits. We found that these inputs first provide GABAergic transmission and later acquire functional glutamatergic transmission as newborn granule cells mature, leading to glutamate/GABA co-transmission. This transition was promoted by activity of supramammillary neurons. These findings reveal a sequential mechanism for establishing dual-transmitter synapses and provide insight into how circuit activity shapes the functional integration of newborn neurons in the adult brain.
