Cingulate thrombospondin 4 protects against neuropathic pain and comorbid anxiodepression via interaction with EAAT2

Patients with neuropathic pain frequently present with emotional disorders. Cellular plasticity within anterior cingulate cortex (ACC) is considered as a key interface linking pain and emotion. However, mounting efforts have been devoted to elucidating intracellular mechanisms of plasticity, how extracellular alterations trigger intracellular changes remains elusive. Thrombospondin (THBS), a key component of extracellular matrix (ECM), is involved in various pathophysiological processes. Here, we show that THBS4 is downregulated in the ACC following peripheral neuropathy. Overexpressing cingulate THBS4 alleviates pain hypersensitivity and anxiodepression. Mechanistic analysis indicates that THBS4 maintains glutamate homeostasis via direct regulation of excitatory amino acid transporter 2 (EAAT2) in astrocytic membrane, further stabilizing abnormal plasticity of pyramidal neurons and eventually producing analgesic, anxiolytic, and antidepressive effects. Taken together, we show THBS4-mediated neuron-astrocyte crosstalk as a key mechanism underlying neuropathic pain and comorbid anxiodepression. Recombinant THBS4 protein represents a promising therapeutic strategy for treatment of neuropathic pain and anxiodepression.