Plasticity of NMDA receptor‐mediated excitatory postsynaptic currents at perforant path inputs to dendrite‐targeting interneurons

Abstract

Key points• NMDA receptors (NMDARs) activated by the neurotransmitter glutamate underlie certain forms of synaptic plasticity in the brain.• These receptors are also subject to plasticity and we have previously described both long-term potentiation (LTP) and long-term depression (LTD) of NMDARs in the principal granule cells of the dentate gyrus region of hippocampus.• The functional significance of these changes in NMDARs on hippocampal network activity depends on whether this occurs only on principal, excitatory neurons or if it also occurs on inhibitory interneurons.• Here we demonstrate differences in NMDAR subtype expression and plasticity in dendrite-targeting interneurons compared to granule cells.• Interneurons displayed LTD of NMDAR-mediated synaptic transmission in response to perforant path activation and had a high threshold for induction of LTP of NMDAR-mediated synaptic currents, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.Abstract Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B-and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms

GluN2D‐containing NMDA receptors inhibit neurotransmission in the mouse striatum through a cholinergic mechanism: implication for Parkinson's disease

“…We used the competitive GluN2C/ GluN2D-preferring antagonists UBP141 and PPDA which display 5-to 10-fold selectivity for GluN2C/GluN2D-containing NMDARs over GluN2A/GluN2B-containing NMDARs, with UBP141 displaying higher selectivity than PPDA (Feng et al 2004;Costa et al 2009). The concentrations of these compounds used in our study were previously shown to inhibit synaptic and extrasynaptic NMDAR-mediated currents in hippocampal and midbrain slices with minimal effect on receptors containing GluN2A or GluN2B (Brothwell et al 2008;Harney et al 2008;Costa et al 2009;Harney and Anwyl 2012). Because GluN2C is absent from the striatum (Bloomfield et al 2007), UBP141 and PPDA likely antagonize the action of NMDA on GluN2Dcontaining NMDARs.…”

“…; Costa et al . ; Harney and Anwyl ). Because GluN2C is absent from the striatum (Bloomfield et al .…”

GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice

“…Interestingly, granule cells synapses are devoid of GluN2D during baseline recording, but GluN2D-containing NMDARs move into the synapse upon induction of long-term potentiation (LTP) of NMDAR-mediated EPSCs (Harney et al, 2008 ). In contrast, induction of long-term depression (LTD) of NMDAR-mediated EPSC in hilar interneurons is associated with removal of synaptic GluN2D (Harney and Anwyl, 2012 ).…”

GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord

“…Synaptic NMDAR responses with very slow decay have been observed in striatal neurons 45 , although pharmacological inhibitors of GluN2D-containing receptors were not tested. In studies from substantia nigra and hippocampal neurons, blockers of GluN2D including UBP-141, UBP-145 and PPDA have been reported to inhibit synaptic NMDAR responses 46 47 48 . A possible explanation put forward for the molecular basis of such synaptic responses has been that these synaptic NMDAR currents may be mediated by triheteromeric NMDARs composed of GluN1, GluN2B, and GluN2D subunits 46 48 .…”