Abstract
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.
Highlights
Synaptic neurotransmission in excitatory neural circuits is governed primarily by the activation of AMPA receptors (AMPARs) and NMDA receptors (NMDARs), two types of ionotropic glutamate receptors located on dendritic spines
These receptors exist as a variety of subtypes, and this molecular heterogeneity is used to explain the diversity in signaling initiated by NMDARs
We have developed a stochastic model of glutamate receptor activation at a single synapse and find that NMDAR subtypes detect different types of glutamate signals
Summary
Synaptic neurotransmission in excitatory neural circuits is governed primarily by the activation of AMPA receptors (AMPARs) and NMDA receptors (NMDARs), two types of ionotropic glutamate receptors located on dendritic spines. Recent evidence shows activation of synaptic NMDA receptors is essential for proper health and maintenance of the neuronal network [7,8,9]. Recent evidence points to the molecular composition of the NMDAR as a possible critical point for regulating the influence of NMDAR activation in networks. The NMDAR composition changes through development, with one diheteromeric form (NR1/NR2B) dominating in immature neurons, eventually augmented by NR2A-containing NMDARs at synaptic sites [16,17,18]. The molecular composition of the receptor, as well as its location, can regulate synaptic plasticity [19,20,21], receptor trafficking [22], and the activation of specific synaptic signaling networks [23,24]. Ongoing discussions in the literature and the considerable limitations and caveats of current pharmacological manipulations of individual subtypes [27] have created the need for alternative methods to better examine the activity of specific NMDAR subtypes
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