DIFFERENT DEVELOPMENTAL MATURATION OF SUPRAMAMMILLARY GLUTAMATERGIC AND GABAERGIC CO-TRANSMISSION INPUTS ONTO ADULT-BORN DENTATE GRANULE CELL SYNAPSES

Recent studies have revealed that the hypothalamic supramammillary nucleus (SuM) neurons project to the dentate gyrus granule cells (GCs) and co-release glutamate and GABA. This subcortical afferent modulates GC firing and contributes to the hippocampal information processing. In the dentate gyrus, adult neurogenesis continues to occur and newborn GCs functionally integrate into the hippocampal circuits. However, the developmental mechanisms of SuM inputs to newborn GCs remain largely unknown.
In this study, to investigate the functional connections of SuM to newborn GCs, we used GAD67-GFP transgenic mice that express GFP in newborn GCs 1-3 weeks postmitosis of the adult hippocampus. AAV-DIO-ChR2(H134R)-mCherry was injected into the SuM of GAD67-GFP mice crossed with VGluT2-Cre mice to optogenetically stimulate SuM inputs in the dentate gyrus. By performing whole-cell patch-clamp recordings from GFP-positive newborn GCs in the acute hippocampal slices, we found that the majority of newborn cells exhibited only GABAergic responses and approximately 20% cells exhibited both GABAergic and glutamatergic responses. By comparing dendritic morphology and synaptic responses, newborn GCs with more complex dendrites exhibit glutamate/GABA synaptic responses, while those with less matured dendrites exhibit only GABAergic responses, suggesting that SuM glutamatergic inputs form after GABAergic synapses during the maturation of GCs. We further found that environmental enrichment or chemogenetic activation of SuM neurons facilitate the formation of glutamate/GABA co-release synapses in newborn GCs. These results indicate that the timing of SuM glutamatergic and GABAergic synapse maturation differs and maturation of SuM-newborn GC synapses is regulated by activity-dependent manner.