Abstract
NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium channels. This mechanism has not yet been studied theoretically. Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. They also shed light on the way by which -amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer’s disease and cerebral ischemia.
Highlights
N-methyl D-aspartate receptors (NMDA-R) are glutamate-gated ion channels and have long been of major interest to neuroscientists owing to their multiple implications in normal neuronal physiology
We propose a simple theoretical model that describes neuronal electrical activity, including the tonic activity of NMDA receptors and a cytosolic calcium compartment (Figure 1A)
This model should be seen as a minimal model allowing the qualitative study of the impact of the coupling between tonic NMDA activity and Ca2+ activated K+channels on the oscillatory regimes of an excitable cell. The core of this model has been experimentally validated on cerebellar granule cells, as it correctly predicts hyperexcitability, when the cytosolic calcium buffering capacity is decreased by by a null mutation suppressing the endogenous calretinin expression, [17] and the transition from regular spiking to bursting, when the calcium buffering capacity of the cytosol is increased by injection of an exogenous buffer [18]. These results already demonstrated that the activation of Ca2+ activated K+channels can provide a tight coupling between excitability and calcium dynamics during spike generation
Summary
N-methyl D-aspartate receptors (NMDA-R) are glutamate-gated ion channels and have long been of major interest to neuroscientists owing to their multiple implications in normal neuronal physiology. Transient activation of NMDA-R at the synaptic level is well known for its key role in the long-term potentiation (LTP) and the long-term depression (LTD) of synaptic transmission, which are believed to be the cellular correlate of learning at the synaptic level [1,2,3,4]. Cerebral ischemia leads to a rise in extracellular glutamate [10] In this condition, NMDA-R appear to play a major role in neuronal calcium influx as the pharmacological blockade of these receptors reduces calcium entry and has a neuroprotective effect [11]
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