Gabapentin prevents synaptogenesis between sensory and spinal cord neurons induced by thrombospondin-4 acting on pre-synaptic Cav α2 δ1 subunits and involving T-type Ca2+ channels

Abstract

Background and purpose: Nerve injury induces concurrent up-regulation of the voltage-gated calcium channel subunit Ca_v α₂ δ₁ and the extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to the development of a neuropathic pain state. Interactions of these proteins promote aberrant excitatory synaptogenesis that contributes to neuropathic pain state development through unknown mechanisms. We investigated the contributions of Ca_v α₂ δ₁ subunits and TSP4 to synaptogenesis, and the pathways involved in vitro, and whether treatment with gabapentin could block this process and pain development in vivo.

Experimental approach: A co-culture system of sensory and spinal cord neurons was used to study the contribution from each protein to synaptogenesis and the pathway(s) involved. Anti-synaptogenic actions of gabapentin were studied in TSP4-injected mice.

Key results: Only presynaptic, but not postsynaptic, Ca_v α₂ δ₁ subunits interacted with TSP4 to initiate excitatory synaptogenesis through a pathway modulated by T-type calcium channels. Ca_v α₂ δ₁ /TSP4 interactions were not required for maintenance of already formed synapses. In vivo, early, but not delayed, treatment with low-dose gabapentin blocked this pathway and the development of the pain state.

Conclusions and implications: Ca_v α₂ δ₁ /TSP4 interactions were critical for the initiation, but not for the maintenance, of abnormal synapse formation between sensory and spinal cord neurons. This process was blocked by early, but was not reversed by delayed, treatment with gabapentin. Early intervention with gabapentin may prevent the development of injury-induced chronic pain, resulting from Ca_v α₂ δ₁ /TSP4-initiated abnormal synapse formation.

Linked articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.