Excitatory neurons are more disinhibited than inhibitory neurons by chloride dysregulation in the spinal dorsal horn

Abstract

Neuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia – the misperception of light touch as painful – occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.

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

“…vs. inhibitory neurons because excitability in the former rely more heavily on inhibition 84 . Altogether, these observations support the prediction that the functional impact of disinhibition is larger where inhibition is more robust.…”

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

“…Spontaneous firing is very low in both WDR and low-threshold mechanosensoryresponsive (LTM) neurons of Sp5C under control conditions; following CCI-IoN, however, spontaneous activity markedly increased in the WDR, but not in the LTM [39]. Moreover, it was recently found that excitatory neurons in laminae I-II in rat lumbar spinal cord showed fast adaptation to light tactile stimuli and very low spontaneous firing, whereas inhibitory neurons with a variety of non-adapting responses had much higher spontaneous activity ( [78]; see also [38]). Should these findings be applicable to the neurons recorded in TCC, it would indicate that these neurons are likely to be excitatory interneurons or projection neurons.…”

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

“…Spontaneous ring is very low in both WDR and low-threshold mechanosensory-responsive (LTM) neurons of Sp5C under control conditions; following CCI-IoN, however, spontaneous activity markedly increased in the WDR, but not in the LTM [39]. Moreover, it was recently found that excitatory neurons in laminae I-II in rat lumbar spinal cord showed fast adaptation to light tactile stimuli and very low spontaneous ring, whereas inhibitory neurons with a variety of non-adapting responses had much higher spontaneous activity ( [78]; see also [38]). Should these ndings be applicable to the neurons recorded in TCC, it would indicate that these neurons are likely to be excitatory interneurons or projection neurons.…”