NMDA receptor kinetics drive distinct routes to chaotic firing in pyramidal neurons.

Introduction: Neuronal firing patterns emerge from complex interactions between intrinsic membrane properties and synaptic receptor dynamics. N-methyl-D-aspartate (NMDA) receptors critically shape calcium influx and synaptic plasticity through their voltage-dependent Mg Methods: We developed a Hodgkin-Huxley-type computational model incorporating NMDA, AMPA, and GABA receptor kinetics to investigate how the NMDA receptor closing rate β Results: The analysis revealed two mechanistically distinct pathways to firing irregularity. Pathway 1 (rapid-deactivation irregularity) emerged under relatively fast NMDA deactivation combined with specific input-frequency conditions, producing deterministic chaos with compromised information encoding. Pathway 2 (prolonged-activation irregularity) resulted from slow NMDA deactivation under weak drive, creating irregularity through sustained receptor activation and calcium influx. An optimal kinetic window emerged at β Discussion: These findings establish NMDA receptor kinetics as fundamental controllers of cortical excitability and information processing. The dual-pathway framework provides mechanistic insights into addiction-related memory formation, where prolonged NMDA activation enables pathological plasticity, and into visual processing disorders, where altered kinetics disrupt retinal function and cortical oscillatory balance. The identification of optimal kinetic windows and frequency-selective GABA modulation suggests therapeutic strategies based on kinetically specific interventions for neuropsychiatric disorders involving NMDA dysfunction.