Abstract
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 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.
Highlights
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)
Rat superficial dorsal horn (SDH) neurons were recorded in whole-cell configuration, by applying a high Cl− load (29 mM) through the recording pipette[19,34,35] (Fig. 1a)
Experimental conditions with high Cl− load were replicated in silico using a virtual neuronal model (Fig. 1d)
Summary
No differences in eIPSCs collapse were observed when slices were pre-incubated with the TrkB antagonist ANA-12 (1 μM51, post-hoc Bonferroni, P > 0.9) nor with the specific KCC2 enhancer CLP257 (5 μM;[10,49] posthoc Bonferroni, P > 0.9; Fig. 6d and Supplementary Fig. 5) Both reversing TrkB-dependent KCC2 downregulation or directly enhancing KCC2 activity, levels off interlaminar differences in inhibitory synaptic plasticity. Way-RM-ANOVA, Finteraction = 0.6, P = 0.9; Supplementary Fig. 7e, f and Fig. 7g) These findings indicate that the propensity to display runaway facilitation in the most superficial part of the SDH is linked to low KCC2 activity resulting from on-going TrkB-dependent signaling. MRGPRD- and TRPV1- fibers were activated by sustained blue light stimulation (2 Hz, 5 min) to the plantar surface of the Distance from IB4 barycentre and YFP peak (μm)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
