Steven A. Prescott

Chloride regulation in the pain pathway

Melzack and Walls Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential (E(anion)), which subsequently impacts fast synaptic inhibition mediated by GABA(A), and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cation-chloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of E(anion) which in turn appears to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury. This review summarizes the current state of knowledge in this area with particular attention to how such findings relate to endogenous mechanisms of hyperalgesia and allodynia and potential applications for therapeutics based on modulation of intracellular Cl(-) gradients or pharmacological interventions targeting GABA(A) receptors.

Impact of Neuronal Properties on Network Coding: Roles of Spike Initiation Dynamics and Robust Synchrony Transfer

Neural networks are more than the sum of their parts, but the properties of those parts are nonetheless important. For instance, neuronal properties affect the degree to which neurons receiving common input will spike synchronously, and whether that synchrony will propagate through the network. Stimulus-evoked synchrony can help or hinder network coding depending on the type of code. In this Perspective, we describe how spike initiation dynamics influence neuronal input-output properties, how those properties affect synchronization, and how synchronization affects network coding. We propose that synchronous and asynchronous spiking can be used to multiplex temporal (synchrony) and rate coding and discuss how pyramidal neurons would be well suited for that task.

Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition.

Fast synaptic inhibition relies on tight regulation of intracellular Cl(-). Chloride dysregulation is implicated in several neurological and psychiatric disorders. Beyond mere disinhibition, the consequences of Cl(-) dysregulation are multifaceted and best understood in terms of a dynamical system involving complex interactions between multiple processes operating on many spatiotemporal scales. This dynamical perspective helps explain many unintuitive manifestations of Cl(-) dysregulation. Here we discuss how taking into account dynamical regulation of intracellular Cl(-) is important for understanding how synaptic inhibition fails, how to best detect that failure, why Cl(-) regulation is energetically so expensive, and the overall consequences for therapeutics.

Single Neuron Firing Properties Impact Correlation-Based Population Coding

Correlated spiking has been widely observed, but its impact on neural coding remains controversial. Correlation arising from comodulation of rates across neurons has been shown to vary with the firing rates of individual neurons. This translates into rate and correlation being equivalently tuned to the stimulus; under those conditions, correlated spiking does not provide information beyond that already available from individual neuron firing rates. Such correlations are irrelevant and can reduce coding efficiency by introducing redundancy. Using simulations and experiments in rat hippocampal neurons, we show here that pairs of neurons receiving correlated input also exhibit correlations arising from precise spike-time synchronization. Contrary to rate comodulation, spike-time synchronization is unaffected by firing rate, thus enabling synchrony- and rate-based coding to operate independently. The type of output correlation depends on whether intrinsic neuron properties promote integration or coincidence detection: “ideal” integrators (with spike generation sensitive to stimulus mean) exhibit rate comodulation, whereas ideal coincidence detectors (with spike generation sensitive to stimulus variance) exhibit precise spike-time synchronization. Pyramidal neurons are sensitive to both stimulus mean and variance, and thus exhibit both types of output correlation proportioned according to which operating mode is dominant. Our results explain how different types of correlations arise based on how individual neurons generate spikes, and why spike-time synchronization and rate comodulation can encode different stimulus properties. Our results also highlight the importance of neuronal properties for population-level coding insofar as neural networks can employ different coding schemes depending on the dominant operating mode of their constituent neurons.

Pain processing by spinal microcircuits: afferent combinatorics.

Pain, itch, heat, cold, and touch represent different percepts arising from somatosensory input. How stimuli give rise to these percepts has been debated for over a century. Recent work supports the view that primary afferents are highly specialized to transduce and encode specific stimulus modalities. However, cross-modal interactions (e.g. inhibition or exacerbation of pain by touch) support convergence rather than specificity in central circuits. We outline how peripheral specialization together with central convergence could enable spinal microcircuits to combine inputs from distinctly specialized, co-activated afferents and to modulate the output signals thus formed through computations like normalization. These issues will be discussed alongside recent advances in our understanding of microcircuitry in the superficial dorsal horn.

Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain

Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from naïve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels. DOI: http://dx.doi.org/10.7554/eLife.02370.001

Subthreshold membrane currents confer distinct tuning properties that enable neurons to encode the integral or derivative of their input.

Neurons rely on action potentials, or spikes, to encode information. But spikes can encode different stimulus features in different neurons. We show here through simulations and experiments how neurons encode the integral or derivative of their input based on the distinct tuning properties conferred upon them by subthreshold currents. Slow-activating subthreshold inward (depolarizing) current mediates positive feedback control of subthreshold voltage, sustaining depolarization and allowing the neuron to spike on the basis of its integrated stimulus waveform. Slow-activating subthreshold outward (hyperpolarizing) current mediates negative feedback control of subthreshold voltage, truncating depolarization and forcing the neuron to spike on the basis of its differentiated stimulus waveform. Depending on its direction, slow-activating subthreshold current cooperates or competes with fast-activating inward current during spike initiation. This explanation predicts that sensitivity to the rate of change of stimulus intensity differs qualitatively between integrators and differentiators. This was confirmed experimentally in spinal sensory neurons that naturally behave as specialized integrators or differentiators. Predicted sensitivity to different stimulus features was confirmed by covariance analysis. Integration and differentiation, which are themselves inverse operations, are thus shown to be implemented by the slow feedback mediated by oppositely directed subthreshold currents expressed in different neurons.

Synaptic inhibition and disinhibition in the spinal dorsal horn.

Nociceptive signals originating in the periphery must be transmitted to the brain to evoke pain. Rather than being conveyed unchanged, those signals undergo extensive processing in the spinal dorsal horn. Synaptic inhibition plays a crucial role in that processing. On the one hand, neuropathy and inflammation are associated with reduced spinal inhibition; on the other hand, the hypersensitivity associated with inflammatory and neuropathic pain can be reproduced by blocking inhibition at the spinal level. To understand the consequences of disinhibition and how to therapeutically reverse it, one must understand how synaptic inhibition normally operates. To that end, this chapter will discuss the structure and function of GABAA and glycine receptors together with the role of associated molecules involved in transmitter handling and chloride regulation. Mechanisms by which inhibition modulates cellular excitability will be described. The chapter will end with discussion of how inhibition goes awry under pathological conditions and what the implications are for the treatment of resulting pain.

Mild KCC2 Hypofunction Causes Inconspicuous Chloride Dysregulation that Degrades Neural Coding

Disinhibition caused by Cl− dysregulation is implicated in several neurological disorders. This form of disinhibition, which stems primarily from impaired Cl− extrusion through the co-transporter KCC2, is typically identified by a depolarizing shift in GABA reversal potential (EGABA). Here we show, using computer simulations, that intracellular [Cl−] exhibits exaggerated fluctuations during transient Cl− loads and recovers more slowly to baseline when KCC2 level is even modestly reduced. Using information theory and signal detection theory, we show that increased Cl− lability and settling time degrade neural coding. Importantly, these deleterious effects manifest after less KCC2 reduction than needed to produce the gross changes in EGABA required for detection by most experiments, which assess KCC2 function under weak Cl− load conditions. By demonstrating the existence and functional consequences of “occult” Cl− dysregulation, these results suggest that modest KCC2 hypofunction plays a greater role in neurological disorders than previously believed.

Inhibitory regulation of the pain gate and how its failure causes pathological pain

Inhibitory neurotransmission in the spinal dorsal horn is at the foundation of the Gate Control Theory of Pain and has been the subject of intense investigation [16; 21]. The dorsal horn is richly endowed with GABAergic and glycinergic neurons and their ionotropic receptors. GABAA receptors are located presynaptically on afferent terminals and both glycine and GABAA receptors are found postsynaptically on dorsal horn neurons [15]. Pharmacologically blocking those receptors can reproduce many features of persistent pain, including mechanical allodynia and spontaneous pain. There is now unequivocal evidence that inhibition in the spinal dorsal horn is pathologically reduced after peripheral nerve injury and persistent inflammation [6; 12; 14]. Importantly, disinhibition can develop via distinct mechanisms. Here we concisely review how disinhibition occurs, focusing on mechanisms affecting postsynaptic inhibition in dorsal horn neurons. We also discuss emerging therapeutic opportunities to restore normal inhibition.