{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNTRK2, which encodes the receptor tyrosine kinase TrkB, plays a pivotal role in the regulation of activity‐dependent synaptic plasticity, neuronal differentiation, and long‐term memory formation. Studies have shown that TrkB activation is required for hippocampal long‐term potentiation and learning, with its expression and posttranslational modification dynamically regulated during neuronal maturation and aging. Genetic mutations in NTRK2, as well as altered transcription of its full‐length and truncated isoforms, can compromise cognitive function, as illustrated by cases of hyperphagic obesity accompanied by learning and memory deficits and by analyses of its regulated expression in distinct hippocampal and cortical regions throughout life. These findings support a model in which fine‐tuned TrkB signaling acts as a “synaptic tag” that integrates both rapid receptor activation and longer term transcriptional programs underlying neuronal plasticity and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in normal neural development and plasticity, altered NTRK2/TrkB signaling has been implicated in a range of neuropsychiatric and neurodegenerative disorders. Abnormal receptor expression and function have been reported in postmortem studies of suicide, schizophrenia, bipolar disorder, major depression, and autism, suggesting that dysregulation of BDNF–TrkB signaling may underlie deficits in neuronal survival, inhibitory neurotransmission, and emotional regulation. In addition, studies describing pathogenic interactions—such as the binding of α‐synuclein to TrkB that impairs its trophic signaling—as well as genetic associations with increased suicidality provide further evidence that disturbances in NTRK2 function contribute to disease vulnerability. Importantly, innovative therapeutic approaches aimed at boosting TrkB signaling (for example, via gene therapy) have shown neuroprotective effects in experimental models of disorders such as glaucoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulated TrkB signaling also provides a mechanistic link to oncogenesis and cancer progression. In a variety of malignancies—including neuroblastoma, ovarian, head and neck, endometrial, and non‐small cell lung cancers, as well as multiple myeloma and breast cancer—overexpression, activating point mutations, and fusion events involving NTRK2 drive tumor cell survival, migration, invasion, and epithelial–mesenchymal transition. Structural analyses of the TrkB kinase domain and the development of pan‐TRK detection assays have paved the way for the use of selective TRK inhibitors as targeted therapies. Moreover, novel small molecule agonists that mimic BDNF, along with advanced gene therapy approaches, are being evaluated to exploit or modulate TrkB signaling in both oncology and neuroprotection, underscoring its therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kiyofumi Yamada, Toshitaka Nabeshima "}, {"type": "b", "children": [{"type": "t", "text": "Brain-derived neurotrophic factor/TrkB signaling in memory processes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1254/jphs.91.267"}], "href": "https://doi.org/10.1254/jphs.91.267"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12719654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12719654"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yuhui Liu, Mario Encinas, Joan X Comella, et al. 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