Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

• DOI: 10.4103/nrr.nrr-d-23-02000
• Publication Date: 2024-05-10T16:00:40Z
• Authors: Xin Yang; Yu-Wen Alvin Huang; John Marshall
• Keywords: 0301 basic medicine; synaptic plasticity; brain-derived neurotrophic factor; autism; Review; neurodevelopmental disorder; postsynaptic density protein-95; 03 medical and health sciences; depression; trkb; angelman syndrome; Neurology. Diseases of the nervous system; neurodegenerative disorder; RC346-429

Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and spine formation to promote learning memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds pre- or postsynaptic TrkB resulting the strengthening synapses, reflected by long-term potentiation. Postsynaptically, association density protein-95 with enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein II phosphatidylinositol 3-kinase-mechanistic target rapamycin required for In this review, we discuss TrkB-postsynaptic coupling as promising strategy magnify towards development novel therapeutics specific neurological disorders. A reduction has been observed neurodegenerative disorders, such Alzheimer's disease Huntington's disease, enhancement could mitigate deficiency neuronal connectivity schizophrenia depression. Treatment is problematic, due poor pharmacokinetics, low brain penetration, side effects from activation p75 neurotrophin truncated TrkB.T1 isoform. Although agonists antibodies that activate are being intensively investigated, they cannot distinguish multiple human splicing isoforms cell type-specific functions. Targeting provides an alternative approach specifically boost localized synaptic sites versus global stimulation risks many adverse effects.