Harnessing pathologic depression through allosteric modulation of neuronal plasticity receptors : Enabling neuroplasticity with psychedelics

Abstract

Depression is a major global health burden, and currently available antidepressants are limited by delayed therapeutic onset and incomplete efficacy. Increasing evidence suggests that antidepressant effects are mediated not only through monoaminergic neurotransmission but also through enhancement of neuronal plasticity involving brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB). Recent studies have further proposed that psychedelics may directly interact with TrkB and modulate neuroplasticity-related signaling pathways. The aim of this study was to establish and optimize assay procedures for the newly introduced Dianthus affinity screening platform for investigation of ligand-TrkB interactions in TrkB-expressing cell lysates, and to perform preliminary evaluation of selected ligands. TrkB abundance and molecular heterogeneity were characterized using Western blotting and ELISA, while receptor glycosylation state was investigated with brefeldin A treatment. The results demonstrated that assay performance was highly dependent on sample preparation. Multiple TrkB-immunoreactive bands consistent with heterogeneous receptor populations and distinct glycosylation states were observed. Preliminary concentration-dependent responses associated with lysergic acid diethylamide (LSD) were detected in TrkB-containing lysates. Together, these findings provide methodological groundwork for future quantitative studies investigating TrkB-targeting antidepressant and psychedelic compounds.