Characterisation of Endogenous Positive Allosteric Modulators of the Tropomyosin Receptor Kinase B
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Serotonin (5-HT) is hypothesised to act as a positive endogenous allosteric modulator of tropomyosin receptor kinase B (TrkB), directly enhancing BDNF-mediated signalling in a manner analogous to psychedelics such as psilocin and LSD, thereby contributing to experience-dependent neuroplasticity. To test this, adult wild-type and TrkB.Y433F mutant mice underwent monocular deprivation (MD) under 5-HT and psilocybin treatment conditions, and visual cortical plasticity was assessed by ocular dominance index (ODI). Resting-state fUS imaging was used to examine alterations in broader functional networks. The right prefrontal cortex, hippocampus, and visual cortex were assessed by western blotting for phosphorylated and total TrkB at Tyr816, and Thr202/Tyr204 levels, as indicators of intracellular signalling.
The findings suggest that the 5-HT may enhance or accompany plasticity following MD. ODI reductions were observed in the visual cortex of 5-HT wild-type mice, consistent with MD-induced visual cortical plasticity. Resting-state fUS further revealed changes in the right midbrain, retrosplenial cortex, and posterior parietal regions, indicating that the effects of MD and 5-HT may extend beyond the primary visual cortex to encompass network-level reorganisation. At the molecular level, increased phosphorylated ERK in the hippocampus despite reduced total ERK suggests altered activation of the MAPK/ERK pathway following combined MD and 5-HT treatment.
Together, these findings are consistent with a role for 5-HT in promoting plasticity-related changes across multiple levels of brain organisation. However, the results remain indirect regarding a 5-HT-TrkB interaction, and future studies should include larger cohorts and binding assays to test whether 5-HT modulates TrkB signalling in a PAM-like manner.