Computational investigation of the changing patterns of subtype specific NMDA receptor activation during physiological glutamatergic neurotransmission

• Published in: PLoS computational biology Vol. 7; no. 6; p. e1002106
• Main Authors: Singh, Pallab, Hockenberry, Adam J, Tiruvadi, Vineet R, Meaney, David F
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2011; Public Library of Science (PLoS)
• Subjects: Analysis of Variance; Biology; CA1 Region, Hippocampal - metabolism; Calcium - metabolism; Computational biology; Computational Biology - methods; Dendritic Spines; Genetic aspects; Glutamate; Glutamic Acid - metabolism; Methyl aspartate; Models, Neurological; Neural transmission; Neurology; Neurons; Physiological aspects; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Signal Transduction; Statistics, Nonparametric; Stochastic models; Stochastic Processes; Synapses - metabolism; Synaptic Transmission - physiology; United States; Calcium; Signal Transduction; Computational Biology; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Glutamic Acid; Analysis of Variance; Stochastic Processes; Dendritic Spines; Statistics, Nonparametric; CA1 Region, Hippocampal; Models, Neurological; Synapses
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1002106

NMDA receptors (NMDARs) are the major mediator of the postsynaptic response during synaptic neurotransmission. The diversity of roles for NMDARs in influencing synaptic plasticity and neuronal survival is often linked to selective activation of multiple NMDAR subtypes (NR1/NR2A-NMDARs, NR1/NR2B-NMDARs, and triheteromeric NR1/NR2A/NR2B-NMDARs). However, the lack of available pharmacological tools to block specific NMDAR populations leads to debates on the potential role for each NMDAR subtype in physiological signaling, including different models of synaptic plasticity. Here, we developed a computational model of glutamatergic signaling at a prototypical dendritic spine to examine the patterns of NMDAR subtype activation at temporal and spatial resolutions that are difficult to obtain experimentally. We demonstrate that NMDAR subtypes have different dynamic ranges of activation, with NR1/NR2A-NMDAR activation sensitive at univesicular glutamate release conditions, and NR2B containing NMDARs contributing at conditions of multivesicular release. We further show that NR1/NR2A-NMDAR signaling dominates in conditions simulating long-term depression (LTD), while the contribution of NR2B containing NMDAR significantly increases for stimulation frequencies that approximate long-term potentiation (LTP). Finally, we show that NR1/NR2A-NMDAR content significantly enhances response magnitude and fidelity at single synapses during chemical LTP and spike timed dependent plasticity induction, pointing out an important developmental switch in synaptic maturation. Together, our model suggests that NMDAR subtypes are differentially activated during different types of physiological glutamatergic signaling, enhancing the ability for individual spines to produce unique responses to these different inputs.