Integration Time in a Subset of Spinal Lamina I Neurons Is Lengthened by Sodium and Calcium Currents Acting Synergistically to Prolong Subthreshold Depolarization

Abstract

Lamina I of the spinal dorsal horn plays an important role in processing and relaying nociceptive information to the brain. It comprises physiologically distinct cell types that process information in fundamentally different ways: tonic neurons fire repetitively during stimulation and display prolonged EPSPs, suggesting operation as integrators, whereas single-spike neurons act like coincidence detectors. Using whole-cell recordings from a rat spinal slice preparation, we set out to determine the basis for prolonged EPSPs in tonic cells and the implications for signal processing. Kinetics of synaptic currents could not explain differences in EPSP kinetics. Instead, tonic neurons were found to express a persistent sodium current, I Na,P , that amplified and prolonged depolarization in response to brief stimulation. Tonic neurons also expressed a persistent calcium current, I Ca,P , that contributed to prolongation but not to amplification. Simulations using NEURON software demonstrated that I Na,P was necessary and sufficient to explain amplification, whereas I Na,P and I Ca,P acted synergistically to prolong depolarization: initial activation of the slower current (I Ca,P ) depended on the faster current (I Na,P ) but maintained activation of the faster current likewise depended on the slower current. Additional investigation revealed that I Na,P and I Ca,P could dramatically increase integration time (Ͼ30ϫ) and thereby encourage temporal summation but at the expense of spike time precision. Thus, by prolonging subthreshold depolarization, intrinsic inward currents allow tonic neurons in spinal lamina I to specialize as integrators that are optimally suited to encode stimulus intensity.

The role of negative conductances in neuronal subthreshold properties and synaptic integration

“…Amplification of EPSP by calcium currents seems to be mediated mostly by T-type Ca 2+ currents rather than by L-type Ca 2+ currents (Liu and Shipley 2008). In addition, calcium currents tend to prolong EPSP decay rather than amplify EPSP amplitude (Prescott and De Koninck 2005).…”

“…the opposite of ideal coincidence detection) that has been observed in different brain regions and which is physiologically relevant since it enhances temporal summation (Prescott and De Koninck 2005). Farries et al (2010) showed in neurons of the subthalamic nucleus that negative slope conductance of I NaP can oppose the positive slope conductance produced by other subthreshold currents, creating a wide region with zero slope conductance which establishes an infinite time constant and strongly reduces the decay phase of EPSPs.…”

“…The amplification of EPSPs by I NaP has been extensively observed in neurons from the neocortex (Andreasen and Lambert 1999;Carter et al 2012;Deisz et al 1991;Fricker and Miles 2000;González-Burgos and Barrionuevo 2001;Hirsch and Gilbert 1991;Lipowsky et al 1996;Rotaru et al 2007;Schwindt and Crill 1995;Stafstrom et al 1985;Stuart and Sakmann 1995;Thomson et al 1988;Zsiros and Hestrin 2005), hippocampus (Ceballos et al 2017;Urban et al 1998;Vervaeke et al 2006), entorhinal cortex (Economo et al 2014;Rosenkranz and Johnston 2007), dorsal cochlear nucleus (Hirsch and Oertel 1988), subthalamic nucleus (Farries et al 2010), hypothalamus (Branco et al 2016), olfactory bulb (Liu and Shipley 2008), dorsal horn of the spinal cord (Prescott and De Koninck 2005), medial superior olive and substantia nigra pars compacta (Yamashita and Isa 2004). In most of these experiments, blocking I NaP with TTX abolished the voltage dependence of the EPSP amplitude and area.…”

“…Pharmacological blockage of calcium currents also decreases the voltage dependence of the amplitude and area of EPSPs (Connelly et al 2016;Gillessen and Alzheimer 1997;Liu and Shipley 2008;Prescott and De Koninck 2005;Urban et al 1998). Amplification of EPSP by calcium currents seems to be mediated mostly by T-type Ca 2+ currents rather than by L-type Ca 2+ currents (Liu and Shipley 2008).…”

Simulation of networks of spiking neurons: A review of tools and strategies

“…1 In 2005, over 50 papers were published on topics such as mechanisms underlying synaptic transmission and plasticity (Banitt et al 2005), modulation of synaptic integration by subthreshold active currents (Prescott and De Koninck 2005), dendritic excitability (Day et al 2005), the role of gap junctions in networks , effects of synaptic plasticity on the development and operation of biological networks (Saghatelyan et al 2005), neuronal gain (Azouz 2005), the consequences of synaptic and channel noise for information processing in neurons and networks (Badoual et al 2005), cellular and network mechanisms of temporal coding and recognition (Kanold and Manis 2005), network states and oscillations (Wolf et al 2005), effects of aging on neuronal function (Markaki et al 2005), cortical recording (Moffitt and McIntyre 2005), deep brain stimulation (Grill et al 2005), and epilepsy resulting from channel mutations (Vitko et al 2005) and brain trauma (Houweling et al 2005). …”