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.

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity

“…It is well established that BDNF release in the SDH is involved in neuropathic pain 10 , 16 , 17 . However, to our knowledge our findings are the first to show chronic BDNF treatment unmasks [Ca 2+ ] i fluctuations in a subpopulation of SDH neurons while depressing activity in others.…”

“…This ‘central sensitization’ is thought to be responsible for the allodynia, hyperalgesia, spontaneous pain and causalgia that characterize neuropathic pain 3 , 15 . Spinal actions of BDNF involve alteration in Cl - gradients such that the normally inhibitory actions of GABA become excitatory 16 , 17 . There is also increased excitatory synaptic drive to putative excitatory neurons 9 , 18 .…”

Intricacies of GABAA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology

“…Moreover, it has been shown that even a robust downregulation of KCC2 activity does not abolish inhibitory postsynaptic potentials (IPSPs) if cellular Cl − regulation is challenged by a Cl − load [ 58 ] and, besides, that this may take place at a low rate. Finally, Ferrini et al recently uncovered a gradient in Cl − extrusion capacity via the superficial dorsal horn of the spinal cord (laminae I-II), which remains concealed under a low Cl − load [ 11 ]. Under a high Cl − load or a heightened synaptic drive, low Cl − extrusion occurred via the expression of KCC2.…”

“…Indeed, in mature neurons, a low [Cl − ] i renders the reversal potential for GABA (E GABA ) more hyperpolarized than the membrane potential (E M ) [ 8 ]. The interaction of GABA with synaptic or extrasynaptic GABA A Rs leads to Cl − influx into the neurons and the hyperpolarization of E M [ 9 , 10 , 11 ]. Under certain circumstances (for example, massive activation), GABA A ergic signaling can be switched from fast hyperpolarization to long-term depolarization of the E M [ 12 , 13 , 14 ].…”

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity

“…This ‘central sensitization’ is thought to be responsible for the allodynia, hyperalgesia, spontaneous pain and causalgia that characterize neuropathic pain (3,15). Spinal actions of BDNF involve alteration in Cl - gradients such that the normally inhibitory actions of GABA become excitatory (16,17). There is also increased excitatory synaptic drive to putative excitatory neurons (9,18).…”