NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model

作者：Burnouf Sylvie; Martire Alberto; Deri**ourg Maxime; Laurent Cyril; Belarbi Karim; Leboucher Antoine; Fernandez Gomez Francisco J; Troquier Laetitia; Eddarkaoui Sabiha; Grosjean Marie Eve; Demeyer Dominique; Muhr Tailleux Anne; Buisson Alain; Sergeant Nicolas; Hamdane Malika; Humez Sandrine; Popoli Patrizia; Buee Luc; Blum David^*

来源：AGING CELL, 2013, 12(1): 11-23.

DOI：10.1111/acel.12018

• Alzheimer's Disease
• brain-derived neurotrophic factor
• hippocampus
• NMDAR
• NR2B
• Src
• Tau
• transgenic mouse

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.

• 出版日期2013-2