Tonic Activation of Extrasynaptic NMDA Receptors Decreases Intrinsic Excitability and Promotes Bistability in a Model of Neuronal Activity

• Main Authors: David Gall, Geneviève Dupont
• Format: Article
• Language: English
• Published: MDPI AG 2019-12-01
• Series: International Journal of Molecular Sciences
• Subjects: calcium; neuron; nmda receptor; excitability; bistability; memory; alzheimer’s disease; cerebral ischemia
• Online Access: https://www.mdpi.com/1422-0067/21/1/206

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 <inline-formula> <math display="inline"> <semantics> <mi>&#946;</mi> </semantics> </math> </inline-formula>-amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer&#8217;s disease and cerebral ischemia.