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Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.

ABSTRACT: GABA_A/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl^-) concentration which is mainly regulated by the K⁺-Cl^- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl^- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl^- load. Under high Cl^- load or heightened synaptic drive, lower Cl^- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl^- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl^- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.

SUBMITTER: Ferrini F

PROVIDER: S-EPMC7414850 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.

Ferrini Francesco F Perez-Sanchez Jimena J Ferland Samuel S Lorenzo Louis-Etienne LE Godin Antoine G AG Plasencia-Fernandez Isabel I Cottet Martin M Castonguay Annie A Wang Feng F Salio Chiara C Doyon Nicolas N Merighi Adalberto A De Koninck Yves Y

Nature communications 20200807 1

GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains conce ...[more]

PMID: 32769979

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Project description:Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavalpha2delta1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavalpha2delta1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavalpha2delta1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavalpha2delta1 transgenic mice. Our data indicated that overexpression of Cavalpha2delta1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavalpha2delta1-mediated spinal sensitization in which elevated Cavalpha2delta1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous stimuli. This spinal sensitization mechanism may mediate at least partially the neuropathic pain states derived from increased pre-synaptic Cavalpha2delta1 expression.

Dataset Information

Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.

Publications

Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.

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