Description
Tau acts in glutamate-induced calcium influx
Guanghao Liu, Yuriy M. Usachev, and Gloria Lee
University of Iowa Carver College of Medicine, Iowa City, IA 52242
Tau, known as an axonal protein, was discovered to have dendritic function where tau would facilitate postsynaptic targeting of Fyn, leading to phosphorylation of the NMDA receptor. Despite this important role, tau knockout mice have displayed no overt behavioral phenotypes or malformations. This lack of deficits has been attributed to increases in other microtubule-associated proteins such as MAP2, which also associates with Fyn. Here we examined the ability of tau to influence glutamate-induced calcium influx through its ability to potentiate Fyn activity and MAP2's association with Fyn as a possible compensating mechanism.
Glutamate-induced calcium influx was measured on primary hippocampal neurons from WT, tau KO, Fyn KO, and tau/Fyn double KO (DKO) mice. While WT and tau KO mice were similar, Fyn KO and DKO mice had significantly less calcium influx, with DKO mice having an even greater reduction relative to Fyn KO. The similarity between calcium influx in WT and tau KO can be explained by our findings that (1) MAP2 levels were increased in tau KO mouse brain and (2) dendrites from tau KO mouse neurons had increased density of MAP2-Fyn complexes, as detected by proximity ligation assay, relative to dendrites from WT mouse neurons. To determine if the MAP2-Fyn complex might resemble the tau-Fyn complex with respect to potentiating Fyn activity, we found that similar to tau, MAP2 can increase Fyn autophosphorylation and Fyn activity. We hypothesize that in tau KO mice, MAP2-Fyn complexes can replace tau-Fyn complexes in the somatodendritic compartment, where activated Fyn mediates calcium influx. Lastly, in comparing Fyn KO and DKO mice, while both had similarly decreased levels of MAP2, DKO had significantly less calcium influx. This suggested that tau has a Fyn-independent role in glutamate-induced calcium influx. In summary, tau acts in mechanisms for glutamate-induced calcium influx, where it can act in a Fyn-independent manner or through Fyn by potentiating Fyn activity, a property that can be mimicked by MAP2 in the absence of tau.
Funding: NIA R01 17753; NIA F30 54134; Alzheimer's Association IIRG-12-241042