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. 2013 Dec;8(5):1098-105.
doi: 10.1007/s11481-013-9476-2. Epub 2013 May 25.

Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory

Holly M Brothers  1 , Isabelle Bardou, Sarah C Hopp, Roxanne M Kaercher, Angela W Corona, Ashley M Fenn, Jonathan P Godbout, Gary L Wenk
Affiliations

Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory

Holly M Brothers et al. J Neuroimmune Pharmacol. 2013 Dec.

Abstract

Impaired memory may result from synaptic glutamatergic dysregulation related to chronic neuroinflammation. GLT1 is the primary excitatory amino acid transporter responsible for regulating extracellular glutamate levels in the hippocampus. We tested the hypothesis that if impaired spatial memory results from increased extracellular glutamate due to age or experimentally induced chronic neuroinflammation in the hippocampus, then pharmacological augmentation of the glutamate transporter GLT1 will attenuate deficits in a hippocampal-dependent spatial memory task. The profile of inflammation-related genes and proteins associated with normal aging, or chronic neuroinflammation experimentally-induced via a four-week LPS infusion into the IV(th) ventricle, were correlated with performance in the Morris water maze following treatment with Riluzole, a drug that can enhance glutamate clearance by increasing GLT1 expression. Age-associated inflammation was qualitatively different from LPS-induced neuro-inflammation in young rats. LPS produced a pro-inflammatory phenotype characterized by increased IL-1ß expression in the hippocampus, whereas aging was not associated with a strong central pro-inflammatory response but with a mixed peripheral immune phenotype. Riluzole attenuated the spatial memory impairment, the elevation of serum cytokines and the decrease in GLT1 gene expression in Aged rats, but had no effect on young rats infused with LPS. Our findings highlight the therapeutic potential of reducing glutamatergic function upon memory impairment in neurodegenerative diseases associated with aging.

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Conflict of interest statement

Conflict of Interest: The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Spatial memory performance
A) Latency to find the hidden platform. LPS-infused controls and Aged controls were impaired (*p < 0.001) compared to young aCSF-infused rats. The performance of Aged rats improved across days only when treated with Ril (†t = 0.035). B) Distance. LPS controls swam a greater distance than aCSF controls and Aged controls (*p ≤ 0.036). C) Swim Speed. Aged rats swam the most slowly (*p ≤ 0.001). D) Thigmotaxis. Aged controls spent the greatest percentage of time within the pool perimeter (*p < 0.001). E) Probe Trial. Both LPS and Aged groups spent less time in the vicinity of the missing platform than aCSF-infused rats (*p ≤ 0.001).
Figure 2
Figure 2. Blood and brain biochemistry
A) Hippocampal gene expression. IL-1β total gene expression relative to aCSF controls was elevated in LPS infused rats as compared to aCSF and Aged rats (*p < 0.001). GLT1 total gene expression relative to aCSF controls was reduced in Aged rats, as compared to aCSF and LPS controls (**p ≤ 0.014), and reversed by Ril treatment (§p = 0.028). B) Hippocampal protein expression. IL-1β and IL-1α protein levels were elevated in LPS infused rats, as compared to aCSF and Aged rats (*p ≤ 0.003). C) Serum protein expression levels. IL-1β and IL-4 were elevated in Aged rats as compared to aCSF rats (*p = 0.017) and IL-10 and Il-2 were elevated in Aged rats as compared to both aCSF and LPS rats (**p ≤ 0.037). D–F) Flow cytometry analysis of CD11b/c-IR microglia in hippocampus. Four weeks of LPS infusion into the IVth ventricle of young rats induced an increase in MHCII (D), TLR4 (E) and GLT1 (F) on a subset of the total microglia population relative to aCSF-infused rats (*p < 0.05). Fractalkine receptor (CX3CR1) levels on the microglia (G) were unchanged.
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