P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway

Abstract

Individuals at risk of developing Alzheimer’s disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation. We found a 40% increase in hippocampal vGLUT, which packages glutamate into vesicles, and has previously been shown to influence glutamate release, and a 40% decrease in hippocampal GLT-1, the major glutamate transporter responsible for removing glutamate from the extracellular space. To determine whether these alterations affected glutamate regulation in vivo, we measured tonic glutamate levels, potassium-evoked glutamate release, and glutamate uptake/clearance in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus. P301L tau expression resulted in a 4- and 7-fold increase in potassium-evoked glutamate release in the DG and CA3, respectively, and significantly decreased glutamate clearance in all 3 regions. Both release and clearance correlated with memory performance in the hippocampal-dependent Barnes maze task. Alterations in mice expressing P301L were observed at a time when tau pathology was subtle and before readily detectable neuron loss. These data suggest novel mechanisms by which tau may mediate hyperexcitability.

Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice

“…The present study extends our previous finding that riluzole rescues the detrimental glutamate dysregulation observed in mice expressing P301L mutant tau (Hunsberger et al 2014a; Hunsberger et al 2015). Here, we have demonstrated that TauP301L mice exhibit larger glutamate transients, primarily due to differences in amplitudes.…”

“…Our previous work suggests that TauP301L mice exhibit an increase in potassium-evoked glutamate release, as well as a decrease in glutamate uptake (Hunsberger et al 2014a; Hunsberger et al 2015). These results are coupled with changes in neuronal proteins, including an increase in the vesicular glutamate transporter responsible for packaging glutamate into vesicles and shown to mediate glutamate release (Moechars et al 2006; Wilson et al 2005), and a decrease in glutamate uptake transporter (GLT-1) expression.…”

“…To prevent mutant tau expression during development, P301L tau expression was suppressed by administering 40 ppm doxycycline hyclate (DOX) in the drinking water until mice were 2.5 months of age (Hunsberger et al 2014a; Hunsberger et al 2014b; Hunsberger et al 2015). Control −/+ mice also received 40 ppm during development and until 2.5 months of age.…”

“…Our previous work suggests that glutamate dysregulation might be driving this increased hyperexcitability and represents a potential therapeutic target (Hunsberger et al 2014a; Hunsberger et al 2015). We have recently shown that the rTg(TauP301L)4510 tau mouse model of AD, containing the proline to leucine mutation in human tau at the 301 st amino acid, exhibits increased potassium-evoked glutamate release and decreased glutamate uptake following application of exogenous glutamate.…”

Tau neurotoxicity and rescue in animal models of human Tauopathies

“…By analogy, microglial pro-inflammatory cytokines can trigger Tau pathology via reactive oxygen species and thus contribute to disease progression [23,39]. Elevated levels of the extracellular neurotransmitter and excitotoxin glutamate were reported in the hippocampus of mutant Tau mice [24]. The question still remains whether these findings represent a cause or an effect of the Tau alterations.…”