Repository logo
 

Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.

Published version
Peer-reviewed

Loading...
Thumbnail Image

Type

Article

Change log

Authors

Sonoyama, Takuhiro 
Stadler, Lukas KJ 
Zhu, Mingyan 
Keogh, Julia M 
Henning, Elana 

Abstract

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.

Description

Keywords

Adolescent, Brain-Derived Neurotrophic Factor, Child, Child, Preschool, Female, Hippocampus, Humans, Male, Neurogenesis, Neuronal Outgrowth, Neurons, Phosphorylation, Protein Kinases, Receptor, trkB, Signal Transduction

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

10

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (098497/Z/12/Z)
Wellcome Trust (207462/Z/17/Z)
Wellcome Trust (208363/Z/17/Z)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (105602/Z/14/Z)
Wellcome Trust (211221/Z/18/Z)
MRC (MC_UU_00014/5)
MRC (MR/P501967/1)
Academy of Medical Sciences (SBF001\1016)
Medical Research Council (MC_PC_12012)