AUTHOR=Hao Rui , Qi Yu , Hou Dong-Ni , Ji Yuan-Yuan , Zheng Chun-Yan , Li Chu-Yu , Yung Wing-Ho , Lu Bai , Huang Ying 

TITLE=BDNF val66met Polymorphism Impairs Hippocampal Long-Term Depression by Down-Regulation of 5-HT3 Receptors

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=11

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2017.00306

DOI=10.3389/fncel.2017.00306

ISSN=1662-5102

ABSTRACT=<p>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 BDNF<sup>Met/Met</sup> 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 GABA<sub>A</sub>Rβ3 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 BDNF<sup>Met/Met</sup> mice, whereas 5-HT2c receptors were up-regulated. Moreover, impaired LTD in BDNF<sup>Met/Met</sup> 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.</p>