The PNN–PTPσ–TrkB signaling gatekeeper model: a putative molecular brake on postsynaptic inhibitory efficacy in chronic neuropathic pain
Year: 2026
Type: article
Abstract: Neuropathic pain maintenance often becomes autonomous of peripheral input once central sensitization is established. We hypothesize that perineuronal nets (PNNs)—extracellular-matrix condensates that, in the spinal dorsal horn, preferentially enwrap lamina I projection neurons—may function as active regulators of postsynaptic inhibitory efficacy, rather than merely passive physical scaffolds. We frame this as a two-cell circuit in which a PV+ interneuron provides the presynaptic gatekeeping input and a PNN-enwrapped lamina I projection neuron constitutes the postsynaptic site of KCC2 loss. Throughout, we use “molecular brake” for the PTPσ-dependent biochemical mechanism and “gatekeeper” for the circuit-level inhibitory function. In this hypothesis-and-theory article, we propose that, by physically restricting neurotrophin diffusion and by maintaining chondroitin-sulfate proteoglycan (CSPG)–protein tyrosine phosphatase sigma (PTPσ)-dependent dephosphorylation of tropomyosin receptor kinase B (TrkB), intact PNNs could preferentially restrain the phospholipase Cγ1 (PLCγ1)–calpain arm while sparing extracellular signal-regulated kinase (ERK)/Akt trophic signaling. Peripheral nerve injury (PNI)-induced PNN degradation could relieve this putative molecular brake; reduced PTPσ-dependent dephosphorylation may then amplify or prolong basal and brain-derived neurotrophic factor (BDNF)-dependent TrkB-PLCγ1 signaling, contributing to downregulation of the K+ –Cl− cotransporter 2 (KCC2) and to a depolarizing shift in the GABA type A (GABA_A)/glycine receptor reversal potential that weakens inhibitory transmission. We explicitly distinguish established findings from hypothetical steps, classify each component of the proposed PNN–PTPσ–TrkB–KCC2 pathway by level of evidence, and formulate falsifiable predictions. We discuss PNN stabilization and KCC2 enhancement as translationally relevant strategies; we discuss the PTPσ inhibitor intracellular sigma peptide (ISP) primarily as an experimental tool—and as a potentially double-edged modulator of TrkB signaling—rather than as a predicted analgesic; ISP is not listed among the therapeutic directions of this model. The proposed convergence of presynaptic (PV–SK) and postsynaptic (KCC2) mechanisms is presented as a circuit-level hypothesis that has not been demonstrated within a single cell population. Finally, we discuss sex-specific divergence. Direct validation of this model in peripheral neuropathic pain models remains an urgent priority.
Authors: Wu Yisen, Chen Xiao, Lu Song
Institution: Huangshi Central Hospital
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225323750