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Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain - PubMed

  • ️Wed Jan 01 2020

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Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain

Tuoxin Cao et al. Cells. 2020.

Abstract

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.

Keywords: TrkB.T1; astrocytes; brain-derived neurotrophic factor (BDNF); neuropathic pain; spinal cord injury; tyrosine receptor kinase B (TrkB).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Tyrosine receptor kinase B (TrkB) receptor isoform expression and signaling in the central nervous system. TrkB.T1 is predominantly expressed in astrocytes, whereas TrkB.TL is highly expressed in neurons. Although TrkB.T2 was reported to be expressed by neurons, its function is unknown. Oligodendrocyte-type-2 astrocyte lineage (O2A progenitor). Rho guanosine diphosphate dissociation inhibitor (RhoGDI1).

Figure 2
Figure 2

TrkB.T1 deletion decreases wide dynamic range neuron hyperexcitability after inflammation. Complete Freund’s Adjuvant (CFA, 20 µL) or saline was injected subcutaneously into the plantar surface of the left hind paw in both TrkB.T1 WT and knockout (KO) mice. After 24 h, wide dynamic range neurons (WDRNs, the number of spikes per second) were recorded in the lumbar enlargement spinal dorsal horn (SDH) ipsilateral to the inflammation. In response to stimulation of von frey filament (VF) and blunt probe, there was significantly less neuronal hyperexcitability of neurons from inflamed KO mice compared to WT. There was no difference between saline-treated WT and KO mice (n = 15 per group). * p < 0.05 WT CFA vs KO CFA with two-way analysis of variance (ANOVA), following Tukey’s multiple comparisons test.

Figure 3
Figure 3

TrkB.T1 contributes to neuropathic pain following spinal cord injury through regulation of cell cycle pathways. Cyclin-dependent kinase (CDK).

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