Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities
| Autor: | Mingyan Zhu, Elana Henning, Beata K. Blaszczyk, Julia M. Keogh, Gary A. Wayman, Takuhiro Sonoyama, Peter Kirwan, Suzanne M. Appleyard, Magdalena Jura, Inês Barroso, I. Sadaf Farooqi, Bas Brouwers, Florian T. Merkle, Marko Hyvönen, David C. DeWitt, Lukas K. J. Stadler, Fuki M. Hisama |
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| Přispěvatelé: | Apollo - University of Cambridge Repository, Stadler, Lukas [0000-0002-7028-4390], Barroso, Ines [0000-0001-5800-4520], Merkle, Florian [0000-0002-8513-2998], Farooqi, Ismaa [0000-0001-7609-3504] |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Neurite Adolescent Molecular biology Neurogenesis Neuronal Outgrowth Synaptogenesis lcsh:Medicine Tropomyosin receptor kinase B Hippocampal formation Biology Hippocampus 03 medical and health sciences Glutamatergic 631/208 0302 clinical medicine Endocrinology Neurotrophic factors Genetics Humans Receptor trkB Phosphorylation 692/163 Receptor lcsh:Science Child Loss function Neurons Multidisciplinary Brain-Derived Neurotrophic Factor musculoskeletal neural and ocular physiology 692/617 lcsh:R article 030104 developmental biology Neurology nervous system Child Preschool lcsh:Q Female 631/378 Neuroscience Protein Kinases 030217 neurology & neurosurgery 631/337 Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020) |
| Popis: | Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf and TrkB leads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised a de novo missense variant in BDNF and seven rare variants in TrkB identified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons. BDNF/TrkB variant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of function BDNF/TrkB variants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders. |
| Databáze: | OpenAIRE |
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