P4–029: Glutamate dysregulation in tau P301L mice

Abstract

Glutamate is the main excitatory neurotransmitter in the brain and is involved in learning and memory, but excess extracellular glutamate, and the subsequent overstimulation of glutamatergic receptors, causes cell death and is implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer's disease (AD). To date, most studies have focused on the role of Aβ in glutamate excitotoxicity. Still unknown is whether tau alone causes pathological changes in glutamate regulation, leading to increased extracellular glutamate concentrations. Instead, most studies implicate extracellular glutamate in the pathophysiology of AD through indirect measures, such as increased signaling of downstream pathways related to excitotoxicity. Thus, it is essential that an increase in extracellular glutamate be confirmed as an early mediator of AD pathology. We used mice producing regulatable levels of human tau carrying the P301L mutation (rTg4510; TauP301L) that exhibit neurofibrillary tangles, neurodegeneration and progressive memory decline. We also used a line expressing regulatable wild-type human tau (rTg21221; TauWT) at levels equivalent to those of the TauP301L mice that show no neurofibrillary tangles, progressive memory decline nor neurodegeneration but allow us to control for human tau overexpression. We used a technically innovative approach, in vivo amperometry coupled to ceramic-based microelectrode arrays (MEAs), which has never been used in a mouse model of AD, in combination with immunoblotting to examine glutamate dysregulation. In TauP301L mice, we found a 65% increase in hippocampal vesicular glutamate transporter (VGLUT) expression and a 20% increase in VGLUT expression the prefrontal cortex (PFC). VGAT, the vesicular transporter for GABA, an inhibitory neurotransmitter, was decreased by 70% in the hippocampus and 40% in the PFC of tauP301L mice. Glutamate dysregulation was observed in TauP301L mice but not tauWT mice. Findings suggest a hyperactive glutamate system in TauP301L mice. We hypothesize that the neurodegeneration observed in our AD mouse model is due, at least in part, to an increase in glutamate activity. Future studies will examine whether decreases in glutamate activity rescue tau pathology and memory deficits.