NMDA receptors enhance the fidelity of synaptic integration (Li and Gulledge 2021)

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Excitatory synaptic transmission in many neurons is mediated by two co-expressed ionotropic glutamate receptor subtypes, AMPA and NMDA receptors, that differ in their kinetics, ion-selectivity, and voltage-sensitivity. AMPA receptors have fast kinetics and are voltage-insensitive, while NMDA receptors have slower kinetics and increased conductance at depolarized membrane potentials. Here we report that the voltage-dependency and kinetics of NMDA receptors act synergistically to stabilize synaptic integration of excitatory postsynaptic potentials (EPSPs) across spatial and voltage domains. Simulations of synaptic integration in simplified and morphologically realistic dendritic trees revealed that the combined presence of AMPA and NMDA conductances reduces the variability of somatic responses to spatiotemporal patterns of excitatory synaptic input presented at different initial membrane potentials and/or in different dendritic domains. This moderating effect of the NMDA conductance on synaptic integration was robust across a wide range of AMPA-to-NMDA ratios, and results from synergistic interaction of NMDA kinetics (which reduces variability across membrane potential) and voltage-dependence (which favors stabilization across dendritic location). When combined with AMPA conductance, the NMDA conductance balances voltage- and impedance-dependent changes in synaptic driving force, and distance-dependent attenuation of synaptic potentials arriving at the axon, to increase the fidelity of synaptic integration and EPSP-spike coupling across neuron state (i.e., initial membrane potential) and dendritic location of synaptic input. Thus, synaptic NMDA receptors convey advantages for synaptic integration that are independent of, but fully compatible with, their importance for coincidence detection and synaptic plasticity.
1 . Li C, Gulledge AT (2021) NMDA receptors enhance the fidelity of synaptic integration eNeuro
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Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism:
Cell Type(s): Dentate gyrus granule GLU cell; Hippocampus CA3 pyramidal GLU cell;
Channel(s): I K; I Na,t;
Gap Junctions:
Receptor(s): AMPA; NMDA;
Transmitter(s): Glutamate;
Simulation Environment: NEURON;
Model Concept(s): Synaptic Integration;
Search NeuronDB for information about:  Dentate gyrus granule GLU cell; Hippocampus CA3 pyramidal GLU cell; AMPA; NMDA; I Na,t; I K; Glutamate;

This simulation builds a fully passive ball-and-stick neuron with a 1,000-µm dendrite with dendritic spines placed every 1 µm. 

1. Compile mod files for synaptic conductances. 

2. Open the "Full_Passive_Single_EPSPs.hoc" file in a text editor.

3. Modify the opening lines of "Full_Passive_Single_EPSPs.hoc" to adjust to the desired RMP (-55 to -85), conductance type (AMPA, NMDA, or Both), and the base name for output files (e.g., "BOTH_85" for runs at an RMP of -85 mV and with both AMPA and NMDA conductances). 

4. Run "Full_Passive_Single_EPSPs.hoc" 

5. Four Output files will be generated, each with 101 traces (for inputs every 10 µm along the dendrite, from 0 to 1000 um from the soma) sampled at 10 kHz. One file will have the somatic EPSPs ("Soma_..."), one will have the dendritic EPSPs ("Dend_..."), and two will have the AMPA or NMDA conductances ("AMPAcond_..." and "NMDAcond_..."). For AMPA+NMDA inputs, traces for total synaptic conductance can be generated by adding the two conductance traces.