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bioRxiv · 10.1101/2025.09.06.674628

NMDA Receptor Kinetics Drive Distinct Routes to Chaotic Firing in Pyramidal Neurons

Borjkhani, M.·BorjKhani, H.·Sharif, M. A.·Bahrami, F.·JanAhmadi, M.
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Abstract

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 Mg2+ block and prolonged activation kinetics. We developed a Hodgkin-Huxley-type computational model incorporating NMDA, AMPA, and GABA receptor kinetics to investigate how NMDA receptor closing rates ({beta}NMDA) and glutamatergic stimulation frequency control neuronal dynamics. Systematic analysis of 2,942,093 inter-spike intervals across 1,961 parameter combinations revealed two mechanistically distinct pathways to firing irregularity. Pathway 1 involves rapid NMDA deactivation ({beta}NMDA > 0.06 ms-1) at elevated stimulation frequencies, producing deterministic chaos with compromised information encoding (entropy: 1.441 bits, mutual information: 0.185 bits). Pathway 2 results from slow NMDA deactivation ({beta}NMDA < 0.02 ms-1) under weak drive, creating irregularity through prolonged receptor activation and sustained calcium influx (entropy: 1.347 bits). An optimal kinetic window emerged at {beta}NMDA = 0.028 ms-1, maximizing information transfer (0.275 bits) while maintaining stable dynamics. Entropy-Lyapunov correlation analysis confirmed deterministic chaos (r = 0.150, p {inverted exclamation} 0.001). Frequency-dependent chaos onset thresholds demonstrated systematic erosion from 0.000 ms-1 at low frequencies to 0.150 ms-1 at high frequencies. GABAergic inhibition provided frequencyselective stabilization, expanding stable parameter space by 34.2 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 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 targeting kinetically-specific interventions for neuropsychiatric disorders involving NMDA dysfunction.

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Borjkhani, M., BorjKhani, H., Sharif, M. A., Bahrami, F., JanAhmadi, M.. 2025-09-11. NMDA Receptor Kinetics Drive Distinct Routes to Chaotic Firing in Pyramidal Neurons. https://doi.org/10.1101/2025.09.06.674628

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