Research Paper

Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex

Wang, Yao Q.^a; Wang, Junshi^a; Xia, Sun-hui^b; Gutstein, Howard B.^c; Huang, Yanhua H.^d; Schlüter, Oliver M.^a; Cao, Jun-Li^b; Dong, Yan^a,d,*

Author Information

^aDepartment of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States

^bJiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China

^cAnesthesiology Institute, Allegheny Health Network, Pittsburgh, PA, United States

^dDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States

^*Corresponding author. Address: Department Neuroscience, University of Pittsburgh, A210 Langley Hall/5th & Ruskin Ave, Pittsburgh, PA 15260, United States. Tel.: 412-624-3140. E-mail address: [email protected] (Y. Dong).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Y.Q. Wang, J. Wang, and S. Xia contributed equally to this work.

PAIN 162(5):p 1322-1333, May 2021. | DOI: 10.1097/j.pain.0000000000002149

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Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become “unsilenced” by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.