Heterosynaptic NMDA receptor plasticity in hippocampal dentate granule cells

The dentate gyrus is a key relay station that controls information transfer from the entorhinal cortex to the hippocampus proper. This process relies heavily on dendritic integration by dentate granule cells (GCs) of excitatory synaptic inputs from the medial and lateral entorhinal cortex via medial and lateral perforant paths (MPP and LPP, respectively). Inputs from the entorhinal cortex onto GCs exhibit activity-dependent long-term plasticity of N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission. However, the properties, underlying mechanisms, and input-specificity of this plasticity remain poorly understood. Here, we examined NMDAR plasticity rules at MPP-GC and LPP-GC synapses using physiologically relevant stimulation patterns in acute hippocampal slices from rats and mice. Unlike MPP-GC synapses, LPP-GC synapses did not express homosynaptic NMDAR-LTP. Additionally, inducing NMDAR-LTP at MPP-GC synapses potentiated NMDAR transmission at distal LPP-GC synapses. The same stimulation protocol induced homosynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-LTP at MPP-GC synapses but heterosynaptic AMPAR-LTD at distal LPP synapses, indicating that NMDAR and AMPAR plasticity are controlled by different plasticity rules. Notably, heterosynaptic but not homosynaptic NMDAR-LTP required Ca²⁺ release from intracellular, ryanodine receptor-dependent Ca²⁺ stores. Lastly, genetic deletion of the GluN2D subunit from GCs or selective antagonism of GluN2D-containing NMDARs abolished heterosynaptic LTP. Heterosynaptic NMDAR-mediated LTP may have important consequences for the dendritic integration of functionally distinct excitatory inputs by dentate granule cells.