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 heavily relies on dendritic integration by dentate granule cells (GCs) of excitatory synaptic inputs from medial and lateral entorhinal cortex via medial and lateral perforant paths (MPP and LPP, respectively). N-methyl-D-aspartate receptors (NMDARs) can contribute significantly to the integrative properties of neurons. While early studies reported that excitatory inputs from entorhinal cortex onto GCs can undergo activity-dependent long-term plasticity of NMDAR-mediated transmission, the input-specificity of this plasticity along the dendritic axis remains unknown. Here, we examined the NMDAR plasticity rules at MPP-GC and LPP-GC synapses using physiologically relevant patterns of stimulation in acute rat hippocampal slices. We found that MPP-GC, but not LPP-GC synapses, expressed homosynaptic NMDAR-LTP. In addition, induction of NMDAR-LTP at MPP-GC synapses heterosynaptically potentiated distal LPP-GC NMDAR plasticity. The same stimulation protocol induced homosynaptic -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-LTP at MPP-GC but heterosynaptic AMPAR-LTD at distal LPP synapses, demonstrating that NMDAR and AMPAR are governed by different plasticity rules. Remarkably, heterosynaptic but not homosynaptic NMDAR-LTP required Ca2+ release from intracellular, ryanodine-dependent Ca2+ stores. Lastly, the induction and maintenance of both homo- and heterosynaptic NMDAR-LTP were blocked by GluN2D antagonism, suggesting the recruitment of GluN2D-containing receptors to the synapse. Our findings uncover a mechanism by which distinct inputs to the dentate gyrus may interact functionally and contribute to hippocampal-dependent memory formation. Significance StatementNMDARs are key players in synaptic plasticity. In addition to their classical role as coincidence detectors and triggers of AMPAR plasticity, there is compelling evidence that NMDARs can undergo activity-dependent plasticity independent of AMPAR plasticity. However, whether NMDAR-plasticity is expressed heterosynaptically remains unclear. Here, in the dentate gyrus of the hippocampus, we show that the induction of burst timing-dependent LTP of NMDAR-mediated transmission at proximal medial perforant path synapses is accompanied by heterosynaptic NMDAR-LTP at lateral perforant path synapses. These findings provide the first evidence for heterosynaptic NMDAR plasticity, which may have important consequences on the dendritic integration of functionally distinct excitatory inputs by dentate granule cells.