Loss of tau and Fyn reduces compensatory effects of MAP2 for tau and reveals a Fyn‐independent effect of tau on calcium

Abstract

Microtubule-associated protein tau associates with Src family tyrosine kinase Fyn and is tyrosine phosphorylated by Fyn. The presence of tyrosine phosphorylated tau in AD and the involvement of Fyn in AD has drawn attention to the tau-Fyn complex.In this study, a tau-Fyn double knockout (DKO) mouse was generated to investigate the role of the complex. DKO mice resembled Fyn KO in novel object recognition and contextual fear conditioning tasks and resembled tau KO mice in the pole test and protection from pentylenetetrazole-induced seizures. In glutamate-induced Ca 2+ response, Fyn KO was decreased relative to WT and DKO had a greater reduction relative to Fyn KO, suggesting that tau may have a Fyn-independent role. Since tau KO resembled WT in its Ca 2+ response, we investigated whether microtubule-associated protein 2 (MAP2) served to compensate for tau, since the MAP2 level was increased in tau KO but decreased in DKO mice. We found that like tau, MAP2 increased Fyn activity. Moreover, tau KO neurons had increased density of dendritic MAP2-Fyn complexes relative to WT neurons. Therefore, we hypothesize that in the tau KO, the absence of tau would be compensated by MAP2, especially in the dendrites, where tau-Fyn complexes are of critical importance. In the DKO, decreased levels of MAP2 made compensation more difficult, thus revealing the effect of tau in the Ca 2+ response. K E Y W O R D Scalcium, Fyn, MAP2, proximity ligation assay, tau

Fyn depletion ameliorates tauP301L-induced neuropathology

“…The 34.3% decrease in NR2B levels was not significant by two-way ANOVA ( p = 0.3607) but was significant if only WT and WT-AAV were compared using the unpaired t-test ( p = 0.0304, SI Table 1 ). Similar to our previous findings [ 46 ], Fyn KO uninjected animals had no changes in PSD95 ( p = 0.4378) or NR2B ( p = 0.9986) when compared to WT uninjected animals (Fig. 7 a,b; SI Table 1 ), indicating that Fyn depletion itself did not cause alterations in synaptic integrity at 6 months of age.…”

“…5 ). However, Fyn KO mice were already known to have abnormal exploratory behavior and cognitive deficits relative to WT mice [ 31 , 46 , 53 ], stemming from Fyn’s role in mediating LTP and memory formation through the phosphorylation of NMDARs [ 23 , 35 , 56 , 83 ]. Therefore, the Fyn KO mice may already be performing at such a low level that further decreases might not be possible no matter the insult, such as tau P301L (also known as the “floor effect”).…”

“…Fyn KO (C57BL/6;S129) mice were obtained from Jackson Laboratories (strain 002385). WT mice were generated by crossing the Fyn KO and Tau KO (C57BL/6, strain 007251) mice, as described [ 46 ]. In this way, the strain of the WT would be closer to that of the Fyn KO, minimizing strain related differences.…”

“…Coronal images were collected and lateral ventricle volume sizes were analyzed with ImageJ [ 8 ]. Quantification was carried out as previously described [ 46 ]. Fyn KO mice were divided by degree of hydrocephalus, with lateral ventricle volume of ≤0.2 units considered normal, 0.2 < x ≤ 2 units as moderate, and > 2 units as severe hydrocephalus.…”

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

“…DKO mice showed significantly increased latency to convulsive seizures and overall reduced seizure severity, but they are not so different from tau KO mice (Figure 1). Another study also corroborated the protective effects of combinatorial Fyn and tau removal against PTZ induced-seizures (Liu et al, 2019). While tau KO mice were similar to DKO mice regarding protective effects against seizures, the Fyn KO mice did not significantly display sufficient anti-seizure effects despite having a reduction of seizure severity by 36 ± 8% compared to WT mice treated with PTZ in this study (Figures 1C-E).…”