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Methods for the Modulation and Analysis of NF-κB-dependent Adult Neurogenesis
Published on: February 13, 2014
BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse
Verna Louhivuori1, Annalisa Vicario, Marko Uutela
1Department of Biomedicine/Physiology, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland.
Abstract:
Fragile X syndrome (FXS) is a common cause of inherited mental retardation and the best characterized form of autistic spectrum disorders. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP), which leads to abnormalities in the differentiation of neural progenitor cells (NPCs) and in the development of dendritic spines and neuronal circuits. Brain-derived neurotrophic factor (BDNF) and its TrkB receptors play a central role in neuronal maturation and plasticity. We studied BDNF/TrkB actions in the absence of FMRP and show that an increase in catalytic TrkB expression in undifferentiated NPCs of Fmr1-knockout (KO) mice, a mouse model for FXS, is associated with changes in the differentiation and migration of neurons expressing TrkB in neurosphere cultures and in the developing cortex. Aberrant intracellular calcium responses to BDNF and ATP in subpopulations of differentiating NPCs combined with changes in the expression of BDNF and TrkB suggest cell subtype-specific alterations during early neuronal maturation in the absence of FMRP. Furthermore, we show that dendritic targeting of Bdnf mRNA was increased under basal conditions and further enhanced in cortical layer V and hippocampal CA1 neurons of Fmr1-KO mice by pilocarpine-induced neuronal activity represented by convulsive seizures, suggesting that BDNF/TrkB-mediated feedback mechanisms for strengthening the synapses were compromised in the absence of FMRP. Pilocarpine-induced seizures caused an accumulation of Bdnf mRNA transcripts in the most proximal segments of dendrites in cortical but not in hippocampal neurons of Fmr1-KO mice. In addition, BDNF protein levels were increased in the hippocampus but reduced in the cortex of Fmr1-KO mice in line with regional differences of synaptic plasticity in the brain of Fmr1-KO mice. Altogether, the present data suggest that alterations in the BDNF/TrkB signaling modulate brain development and impair synaptic plasticity in FXS.
Insights
Fragile X syndrome (FXS) involves loss of FMRP, impacting neural development. Altered BDNF/TrkB signaling in FXS mice disrupts neuronal differentiation and synaptic plasticity, contributing to cognitive deficits.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and a prominent form of autism spectrum disorder.
- FXS results from the absence of functional fragile X mental retardation protein (FMRP), leading to aberrant neural progenitor cell (NPC) differentiation and impaired development of neuronal structures.
- Brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) are critical for neuronal maturation and synaptic plasticity.
Purpose of the Study:
- To investigate the role of BDNF/TrkB signaling in the context of FMRP deficiency.
- To examine how the absence of FMRP affects BDNF/TrkB-mediated neuronal differentiation, migration, and synaptic function in a mouse model of FXS.
Main Methods:
- Utilized Fmr1-knockout (KO) mice, a model for FXS.
- Analyzed neurosphere cultures and developing brain tissue (cortex and hippocampus).
- Assessed BDNF and TrkB expression, intracellular calcium signaling, and mRNA/protein localization following pilocarpine-induced seizures.
Main Results:
- Increased catalytic TrkB expression in undifferentiated NPCs of Fmr1-KO mice correlated with altered neuronal differentiation and migration.
- Aberrant calcium responses to BDNF and ATP in differentiating NPCs suggest cell subtype-specific defects.
- Dendritic targeting of Bdnf mRNA was enhanced in Fmr1-KO mice, particularly after pilocarpine-induced seizures, indicating compromised synaptic strengthening mechanisms.
- BDNF protein levels showed regional differences (increased in hippocampus, decreased in cortex) in Fmr1-KO mice.
Conclusions:
- Altered BDNF/TrkB signaling pathways are implicated in the aberrant brain development observed in FXS.
- These signaling disruptions contribute to impaired synaptic plasticity, offering potential therapeutic targets for FXS.
- Cell subtype-specific alterations in BDNF/TrkB signaling during early neurodevelopment are a key feature of FXS.
