Abstract
Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors.
Highlights
Glutamate is the main excitatory neurotransmitter in mammalian brain and mediates its effects through the activation of two major classes of receptors, the ionotropic and metabotropic glutamate receptors
Model of a CA1 glutamatergic synapse Our modeling framework consists of a CA1 dendritic spine divided into four distinct compartments, i.e., cleft, post-synaptic density (PSD), cytosol and endoplasmic reticulum (ER), with volumes of 0.0015, 0.002, 0.02 and 0.002 mm3, respectively in accordance with the three dimensional structure of CA3-CA1 pyramidal cell synapses [15,16] (Figure 1)
The model incorporates AMPA and NMDA receptors as well as metabotropic glutamate receptors type I. It includes the intracellular cascade activated by mGluR type I (mGluRI), and a number of elements involved in calcium signaling
Summary
Glutamate is the main excitatory neurotransmitter in mammalian brain and mediates its effects through the activation of two major classes of receptors, the ionotropic (iGluRs) and metabotropic glutamate receptors (mGluRs). Considering the complexity of calcium homeostasis and the implication of mGluRI in various brain functions as well as disease states [12,13,14], there is a need to better understand the relative contribution of these mechanisms to calcium dynamics under different experimental conditions. Direct measurements of these parameters at a single synapse are extremely difficult, and experimental control over many synaptic mechanisms is still currently impossible, motivating the use of a biophysically realistic model of receptor activation at a single synapse. Our results indicate that the contribution of mGluRI to calcium dynamics is dependent on both its synaptic localization and the stimulation frequency, and reveal interesting receptor interactions at the level of IP3 dynamics
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