Open AccessNMDA receptor dysfunction contributes to impaired brain‐derived neurotrophic factor‐induced facilitation of hippocampal synaptic transmission in a T au transgenic model
Author(s) -
Burnouf Sylvie,
Martire Alberto,
Derisbourg Maxime,
Laurent Cyril,
Belarbi Karim,
Leboucher Antoine,
FernandezGomez Francisco J.,
Troquier Laetitia,
Eddarkaoui Sabiha,
Grosjean MarieEve,
Demeyer Dominique,
MuhrTailleux Anne,
Buisson Alain,
Sergeant Nicolas,
Hamdane Malika,
Humez Sandrine,
Popoli Patrizia,
Buée Luc,
Blum David
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12018
Subject(s) - tropomyosin receptor kinase b , neuroscience , neurotrophic factors , nmda receptor , synaptic plasticity , hippocampus , long term potentiation , brain derived neurotrophic factor , hippocampal formation , biology , neurotransmission , receptor , biochemistry
Summary While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in A lzheimer'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 ‐ T au22 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 T au mice together with a reduced phosphorylation of NR 2B 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 ‐ T au22 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.