Excitatory selective LTP of supramammillary glutamatergic/GABAergic cotransmission potentiates dentate granule cell firing

Emerging evidence indicates that the functionally opposing neurotransmitters, glutamate and GABA, are coreleased from the same presynaptic terminals in some adult brain regions. The supramammillary nucleus (SuM) is one region that coreleases glutamate and GABA in the dentate gyrus (DG) through its afferents. Although the SuM-DG pathway has been implicated in various brain functions, little is known about the functional roles of the peculiar features of glutamate/GABA corelease. Here, we show that depolarization of granule cells (GCs) triggers postsynaptic long-term potentiation (LTP) of glutamatergic, but not GABAergic, cotransmission at SuM-GC synapses. Moreover, the burst activity of perforant-path inputs heterosynaptically induces LTP at excitatory SuM-GC synapses. This non-Hebbian LTP requires postsynaptic Ca(2+) influx, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, and exocytosis of AMPA receptors. Glutamatergic transmission-selective expression of LTP increases the excitatory drive such that SuM inputs become sufficient to discharge GCs. Our results highlight a form of LTP, which dynamically and rapidly changes the glutamatergic/GABAergic cotransmission balance and contributes to DG network activity.