Peripheral nerve injury increases the probability of thalamocortical burst firing remotely via microglia-dependent enhancement of tonic inhibition.

Burst firing and dysrhythmia of thalamocortical (TC) neurons are involved in central pain. In neuropathic pain, peripheral nerve damage can trigger abnormal firing of distant TC neurons. Here, in the mouse whisker somatosensory thalamus, we aimed to identify the regulatory mechanisms for TC firing induced by an infraorbital nerve cut (IONC). IONC hyperpolarized resting membrane potentials and reduced input resistances of TC neurons. These changes are related to accelerated burst firing and increased spike-frequency adaptation during depolarization. In addition, IONC decreased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by attenuating hyperpolarization-induced voltage sag and shifting the activation potential towards more hyperpolarized potentials. Consistently, IONC reduced the number of rebound spikes after hyperpolarization. We previously reported that IONC-induced neuronal and glial changes in thalamic and brainstem whisker regions are necessary for the development of mechanical hypersensitivity: increased thalamic tonic inhibition via extrasynaptic GABAA receptors and aggregated microglia in the brainstem projecting to the thalamus. We found that genetic ablation of extrasynaptic GABAA receptors in TC neurons prevented IONC-induced changes in membrane properties, and that brain-wide microglial ablation exhibited the same tendency. Whereas brainstem local microglial ablation prevented IONC-induced enhancement of tonic inhibition, thalamic local microglial ablation failed to cause the same phenomenon. Thus, our results suggest that IONC alters distant TC firing via microglial and tonic inhibitory interactions along the ascending pathway. By using these remote mechanisms, peripheral nerve injury may cause central sensitization of neuropathic pain.