NMDA Receptor-Based Voltage Dependent Synaptic Plasticity Model of Learning at the Hippocampal Ca3-Ca1 Synapses

Abstract

Synaptic plasticity is believed to be a biological basis of learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) are the most common forms of synaptic plasticity, induced by a pre- and postsynaptic neuronal activity, and refer to the strengthening and weakening of synaptic weight. We develop a NMDA receptor-based voltage dependent synaptic plasticity model for synaptic modifications at Schaffer-collateral synapses onto hippocampal CA1 pyramidal neuron. The model incorporates the NMDA receptor-based function and is able to capture dynamics of the NMDA NR2A and NR2B receptor subunits without explicitly modeling dendritic spine intracellular calcium dynamics, a local trigger of synaptic plasticity. The model was embedded into a detailed compartmental model of a hippocampal CA1 pyramidal cell to investigate the dependence of synaptic modifications on the NMDA receptor functioning for spatially and temporally specific inputs. The present study reproduces experimentally observed outcomes of LTP and LTD induction, as well as standard STDP protocol, analyzes the sensitivity of the model and predicts the influence of synaptic location on synaptic modifications and explains the impaired learning during theta cycles in the presence of the NMDA receptor hypofunction. During experiments it was observed that high frequency stimulation leads to LTP induction and EPSPs increase up to 180%, while low frequency stimulation induces LTD which leads to EPSP decrease up to 54%. The developed NMDA receptor-dependent synaptic plasticity model can be used for experimentally testable predictions and be applied in large scale simulations for modeling hippocampal networks in health and disease.