Holly Hunsberger: Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

The overall focus of my research is to identify the mechanistic links underlying learning and memory in the context of aging and Alzheimer’s disease (AD), with emphasis on determining neuropsychiatric symptoms and sex differences in disease progression. Under the supervision of Dr. Miranda Reed at West Virginia University, my graduate work focused primarily on four lines of inquiry: (1) identification of memory tasks sensitive to early synaptic alterations in transgenic mouse models of AD, (2) identification of early alterations in glutamatergic signaling using a novel technology, microelectrode arrays (MEAs) coupled to amperometry, (3) targeting the glutamatergic system with novel drug treatments to prevent AD-related memory deficits and early synaptic alterations, and (4) examining the role of glutamate in the robust and protracted hippocampal hyperexcitability resulting from viral infections. Alzheimer’s disease (AD) is a neurodegenerative disorder that targets vulnerable neural networks, particularly those involved in learning and memory. Though originally this hyperactivity was believed to serve a compensatory function for deteriorating circuitry, more recent evidence suggests this hyperactivity may be indicative of excitotoxicity, could directly contribute to cognitive impairment, and may even be permissive for the development of AD. Individuals at risk for Alzheimer’s disease (AD) often exhibit hippocampal hyperexcitability in the years preceding AD diagnosis. Our previous work suggests a dysregulation of glutamate neurotransmission may mediate this hyperexcitability. Furthermore, glutamate dysregulation correlates with memory deficits in the commonly used rTg(TauP301L)4510 tau mouse model of AD. This mouse model exhibits tau tangle pathology which is one of the hallmarks of AD in human patients. The goal of the current study was to determine whether improved regulation of glutamate would rescue the cognitive deficits and AD-related pathology associated with mutant P301L tau expression. AD mice were treated with riluzole, an FDA-approved drug for ALS that lowers extracellular glutamate levels by decreasing glutamate release and increasing glutamate uptake. Using microelectrode array (MEA) technology, we examined glutamate release and uptake in the dentate gyrus (DG), CA3 and CA1 subregions of the hippocampus and correlated these measures with learning and memory performance in the Morris water maze. Riluzole-treated AD mice exhibited improved cognitive performance associated with a decrease in glutamate release and an increase in glutamate uptake. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation.These findings further elucidate the changes in glutamate regulation associated with tau pathology, open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD, and are an important first step toward the development of an off-label, proof-of-concept investigation of riluzole in AD patients.

Article can be found here: https://www.ncbi.nlm.nih.gov/pubmed/26146790

Holly Hunsberger (hh2694@cumc.columbia.edu)