Spinal cord injury‐induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down‐regulation of the chloride transporter KCC2 in rat

Abstract

Most spinal cord injury (SCI) patients suffer from chronic pain. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. The spinal superficial dorsal horn (SDH) contains neuronal circuits capable of modulating primary afferent information involved in pain processing. KCC2 is an isoform of the K + -Cl − cotransporter that contributes to the regulation of transmembrane anion gradient which plays a key role in shaping GABA A receptor-mediated signalling in the CNS. We tested the hypothesis that SCI causes down-regulation of KCC2 distal to the injury and contributes to the neuronal hyperresponsiveness and pain-related behaviours. SCI was a hemisection at T 13 level of adult Sprague-Dawley rats. Spinal sagittal slices with attached dorsal roots (DR) were prepared from L 4 to L 6 level. The reversal potentials of GABA responses (E GABA ) and DR-evoked IPSPs and EPSPs of L 4−6 SDH neurones in sham-operated and SCI rats were compared using gramicidin-perforated patch-clamp recordings. Here we report that thoracic SCI-induced down-regulation of KCC2 in the lumbar SDH parallels the development of allodynia. The subsequent changes of E GABA in SDH neurones attenuate the GABA A receptor-mediated inhibitory synaptic transmission. These changes cause certain normally subthreshold primary A and C fibre inputs to evoke action potential output in SDH neurones. We conclude that SCI induces KCC2 down-regulation and subsequent changes of E GABA in the SDH below the injury site. The resulting disinhibition unmasks normally ineffective SDH neuronal circuits and may contribute to the below-level central pain-related behaviours after incomplete SCI.

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

“…These neurons exhibited transient firing in response to sustained depolarizing current ( Figure 3C). The physiological and morphological features of the postsynaptic neurons in all 18 pairs closely match those of lamina II TC neurons identified previously (7,8,24,26,30,31). The excitatory synaptic transmission from PKCγ + neurons to TC neurons was less reliable, as indicated by a relatively high rate of transmission failure (23% ± 5%; n = 18; Table 1), and exhibited short-term depression induced by repetitive APs in 100-ms intervals (paired-pulse ratio: 0.6 ± 0.2, n = 18; Figure 3A, Supplemental Figure 3, and Table 1).…”

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Invetigators have speculated that the partial denervation of subicular cells in TLE, due to the loss of their pre-synaptic CA1 subfield inputs region, induces a return to an immature pattern of Cl − homeostasis. This view is supported by experimental evidence in which it was shown that following damage to afferents in the spinal cord, BDNF liberated by microglia activates trkB receptors leading to a KCC2 down-regulation and a depolarizing shift in GABAergic reversal potentials associated with pathological pain responses (Price et al, 2005;Lu et al, 2008). It has also been shown that experimentally induced interictal activity in hippocampal slices maintained in vitro, downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl − extrusion (Rivera et al, 2002(Rivera et al, , 2004Blaesse et al, 2009).…”

Functional Recovery after Lesion of a Central Pattern Generator

“…Inhibitory synapses can become excitatory if the reversal potential for Cl Ϫ is shifted to a more positive potential. This can occur by downregulation of Cl Ϫ transporters, as was observed in response to spinal cord injury (Lamsa and Taira, 2003;Payne et al, 2003;Lu et al, 2008;Vinay and JeanXavier, 2008). This could be a component of the recovery response because it recapitulates an earlier developmental state (Jean-Xavier et al, 2006.…”