Abstract
Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity and cognitive functions. BDNF val66met polymorphism, a human single-nucleotide polymorphism (SNP) in the pro-domain of BDNF gene, is associated with deficits in activity-dependent BDNF secretion and hippocampus-dependent memory. However, the underlying mechanism remains unclear. Here we show that in the BDNFMet/Met mouse line mimicking the human SNP, BDNF expression in the hippocampus was decreased. There was a reduction in the total number of cells in hippocampal CA1 region, while hippocampal expression of mRNAs for NR2a, 2b, GluR1, 2 and GABAARβ3 subunits were up-regulated. Although basal glutamatergic neurotransmission was unaltered, hippocampal long-term depression (LTD) induced by low-frequency stimulation was impaired, which was partially rescued by exogenous application of BDNF. Interestingly, 5-HT3a receptors were down-regulated in the hippocampus of BDNFMet/Met mice, whereas 5-HT2c receptors were up-regulated. Moreover, impaired LTD in BDNFMet/Met mice was reversed by 5-HT3aR agonist. Thus, these observations indicate that BDNF val66met polymorphism changes hippocampal synaptic plasticity via down-regulation of 5-HT3a receptors, which may underlie cognition dysfunction of Met allele carriers.
Highlights
Brain-derived neurotrophic factor (BDNF), a member of nerve growth factor family, plays an important role in the development and function of the central nervous system (CNS; Huang and Reichardt, 2001)
Using Quantigene assay, we found that expression of BDNF mRNA was down-regulated in the hippocampus of BDNFMet/Met mice (3 or 6-week-old, Figure 1A; P < 0.0001 for Quantigene assay; unpaired t-test)
In the present study, using BDNFMet/Met mice, we investigated the effect of BDNF val66met polymorphism on synaptic plasticity and the underlying mechanism
Summary
Brain-derived neurotrophic factor (BDNF), a member of nerve growth factor family, plays an important role in the development and function of the central nervous system (CNS; Huang and Reichardt, 2001). A common single nucleotide polymorphism (SNP) rs6265 at nucleotide 196 (G/A) at codon 66 in the pro-domain of human BDNF gene converts the amino acid valine (Val) to methionine (Met). This amino acid substitution affects dendritic trafficking of pro-BDNF and alters the regulated secretion of BDNF (Egan et al, 2003; Chen et al, 2006). The allele frequency varies from 0.55% to 43.6% in Africa, Europe and Asia (Petryshen et al, 2010) Human subjects with this SNP exhibit deficits in short-term episodic memory, suggesting the importance of activity-dependent BDNF secretion. It has been revealed that in the IL-mPFC pyramidal neurons of BDNFMet/Met mice, spiketiming-dependent plasticity (STDP) is absent, and NMDA receptor-mediated synaptic transmission is impaired (Pattwell et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
