A model of NMDA receptor-mediated activity in dendrites of hippocampal CA1 pyramidal neurons.
1. The role of synaptic activation of NMDA (N-methyl-D-aspartate) receptor-mediated conductances on CA1 hippocampal pyramidal cells in short-term excitability changes was studied with the use of a computational model. Model parameters were based on experimental recordings from dendrites and somata and previous hippocampal simulations. Representation of CA1 neurons included NMDA and non-NMDA excitatory dendritic synapses, dendritic and somatic inhibition, five intrinsic membrane conductances, and provision for activity-dependent intracellular and extracellular ion concentration changes. 2. The model simulated somatic and dendritic potentials recorded experimentally. The characteristic CA1 spike afterdepolarization was a consequence of the longitudinal spread of dendritic charge, reactivation of slow Ca(2+)-dependent K+ conductances, slow synaptic processes (NMDA-dependent depolarizing and gamma-aminobutyric acid-mediated hyperpolarizing currents) and was sensitive to extracellular potassium accumulation. Calcium currents were found to be less important in generating the spike afterdepolarization. 3. Repetitive activity was influenced by the cumulative activation of the NMDA-mediated synaptic conductances, the frequency-dependent depression of inhibitory synaptic responses, and a shift in the potassium reversal potential. NMDA receptor activation produced a transient potentiation of the excitatory postsynaptic potential (EPSP). The frequency dependence of EPSP potentiation was similar to the experimental data, reaching a maximal value near 10 Hz. 4. Although the present model did not have compartments for dendritic spines, Ca2+ accumulation was simulated in a restricted space near the intracellular surface of the dendritic membrane. The simulations demonstrated that the Ca2+ component of the NMDA-operated synaptic current can be a significant factor in increasing the Ca2+ concentration at submembrane regions, even in the absence of Ca2+ spikes. 5. Elevation of the extracellular K+ concentration enhanced the dendritic synaptic response during repetitive activity and led to an increase in intracellular Ca2+ levels. This increase in dendritic excitability was partly mediated by NMDA receptor-mediated conductances. 6. Blockade of Ca(2+)-sensitive K+ conductances in the dendrites increased the size of EPSPs leading to a facilitation of dendritic and somatic spike activity and increased [Ca2+]i. NMDA receptor-mediated conductances appeared as an amplifying component in this mechanism, activated by the relatively depolarized membrane potential. 7. The results suggest that dendritic NMDA receptors, by virtue of their voltage-dependency, can interact with a number of voltage-sensitive conductances to increase the dendritic excitatory response during periods of repetitive synaptic activation. These findings support experimental results that implicate NMDA receptor-mediated conductances in the short-term response plasticity of the CA1 hippocampal pyramidal neuron.
Pongrácz
F
F
Section of Neurobiology, Yale University School of Medicine, New Haven 06510.
Poolos
N P
NP
Kocsis
J D
JD
Shepherd
G M
GM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003712:Dendrites / Q000502:physiology*; D005071:Evoked Potentials / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D007700:Kinetics; D008954:Models, Biological; D009431:Neural Conduction / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology; D013569:Synapses / Q000502:physiology
D015221:Potassium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D002118:Calcium