NMDA Channels Together With L-Type Calcium Currents and Calcium-Activated Nonspecific Cationic Currents Are Sufficient to Generate Windup in WDR Neurons

Abstract

Windup is characterized as a frequency-dependent increase in the number of evoked action potentials in dorsal horn neurons in response to electrical stimulation of afferent C-fibers. This phenomenon was first described in the mid-60s, but the core mechanisms behind it still remain elusive. Several factors affecting its dynamics have been identified, but the distinction between modulating mechanisms from generating mechanisms is not always clear. Several mechanisms contribute to the excitation of dorsal horn neurons exhibiting windup, and one of our main aims was to help making this distinction. The approach presented here relies on mathematical and computational analysis to study the mechanism(s) underlying windup. From experimentally obtained windup profiles, we extract the time scale of the facilitation mechanisms that may support the characteristics of windup. Guided by these values and using simulations of a biologically realistic compartmental model of a wide dynamic range (WDR) neuron, we are able to assess the contribution of each mechanism for the generation of action potentials windup. We show that the key mechanisms giving rise to windup is the temporal summation of N-methyl-d-aspartate (NMDA) long-lasting postsynaptic responses taking place on top of a membrane potential cumulative depolarization. Calcium-activated nonspecific cationic currents driven by calcium influx from L-type calcium channels and synaptic currents support this cumulative depolarization and plateau formation in WDR neuron membrane potential. The effects of different nonhomogeneous stimulation protocols are explored, and their important role in clarifying many aspects of the windup generation is shown. The models are used to produce several predictions that can be tested experimentally.