TrkB

Pharmacological exploitation of neurotrophins and their receptors to develop novel therapeutic approaches against neurodegenerative diseases and brain trauma

Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.

Malignant synaptic plasticity in pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. Cell membrane protein capture (via biotinylation) and live imaging of pH sensitive GFP-tagged AMPAR subunits demonstrate an increase of calcium permeable channels at the tumors postsynaptic membrane in response to BDNF. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicates the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage normal mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

Neuronal plasticity and neurotrophin signaling as the common mechanism for antidepressant effect

Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.

FKBP51 REGULATES BDNF/TRKB SIGNALING AND STRESS-DRIVEN SYNAPTIC PLASTICITY

FENS Forum 2026

PSYCHEDELICS AND CLASSICAL ANTIDEPRESSANTS AS POSITIVE ALLOSTERIC MODULATORS OF TRKB

FENS Forum 2026

ALTERED BDNF AND TRKB LEVELS IN CEREBELLAR PURKINJE CELLS MAY CONTRIBUTE TO ATAXIA IN A CHRISTIANSON SYNDROME MOUSE MODEL

FENS Forum 2026

FLUOXETINE ENHANCES TRKB EXPRESSION AND FUNCTION TO RESCUE MOTOR COORDINATION DEFICITS IN A MOUSE MODEL OF SPINOCEREBELLAR ATAXIA TYPE 6

FENS Forum 2026

TRKB–DOCK3 SIGNALING COORDINATES WAVE1-DEPENDENT ACTIN DYNAMICS AND HAUS7-MEDIATED AXON BRANCHING IN THE ADULT CNS

FENS Forum 2026

DECIPHERING THE ROLES OF TAT-TRKB AND TRKB-ICD IN MICROGLIAL FUNCTION WITHIN THE ALZHEIMER’S DISEASE CONTEXT

FENS Forum 2026

BDNF RECEPTOR DYSREGULATION IN ALZHEIMER'S-DISEASE: EXTRACELLULAR VESICLE-MEDIATED TRANSPORT OF A SYNAPTOTOXIC TRKB FRAGMENT

FENS Forum 2026

TRKB-DEPENDENT KINASE SIGNALING REGULATES EXCITABILITY OF MEDIAL PREFRONTAL CORTEX PYRAMIDAL NEURONS

FENS Forum 2026

TRKB ACTIVATION AS A NOVEL TARGET FOR DRUG RESISTANT TEMPORAL LOBE EPILEPSY: FROM ANIMAL MODELS TO THE HUMAN EPILEPTIC BRAIN

FENS Forum 2026

SEX- AND REGION-SPECIFIC TRKB ISOFORM IMBALANCE AND AMYLOID-BETA MODULATION IN 5XFAD MICE

FENS Forum 2026

The S1PR2-CCL2-BDNF-TrkB pathway mediates neuroinflammation, alterations in GABAergic neurotransmission and motor incoordination in hyperammonemic rats

BDNF/TrkB signalling, in cooperation with muscarinic signalling, retrogradely regulates PKA pathway to phosphorylate SNAP-25 and Synapsin-1 at the NMJ

FENS Forum 2024

5xFAD mice present memory impairments and reduced TrkB-FL levels that were reverted after TAT-TrkB administration

Melatonin deficiency related to pinealectomy has an age-specific impact on memory decline in rats through ERK/CREB/BDNF/TrkB signaling in the hippocampus

FENS Forum 2024

A potential new source of TrkB dysregulation: Microglia possess the machinery for BDNF receptor cleavage

FENS Forum 2024

TrkB receptor interacts with mGlu2 receptor and mediates antipsychotic-like effects of mGlu2 receptor activation in the mouse

FENS Forum 2024

Differential effects of psychedelics and classical antidepressants on TrkB dimerization and neurotrophic signalling

FENS Forum 2024

Ageing-associated alterations in BDNF/TrkB pathway involving PKC and synaptic targets of the Neuromuscular Junction

Anterograde delivery of Rab10-organelles regulates the sorting of internalised TrkB for retrograde axonal transport

BDNF/TrkB pathway activation in D1 receptor-expressing striatal projection neurons plays a protective role against L-DOPA-induced dyskinesia

Dose-dependent effects of ketamine on electrophysiological network activity and TrkB-ERK signaling in cortical neuronal culture

Exercise acts via BDNF-TrkB signalling to rescue behavioural and Purkinje cell firing deficits in a mouse model of spinocerebellar ataxia type 6

Interaction of BDNF-TRKB and corticosteroids signaling pathways

Mirtazapine rescues neuronal atrophy in Rett syndrome through TrkB transactivation via LPA-receptor

Novel insights into antidepressant-induced TrkB signaling

Physical activity adapts the BDNF/TrkB signalling towards a molecular fatigue-resistant phenotype at the NMJ