Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse

Abstract

The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a beta-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

“…Consistent with this view, we found that chronic treatment with Cef (i.p., 200 mg/kg) not only increased GLT-1 expression in LA but also reversed the impairment of LTP and fear memory in AQP4 KO mice. Our behavioral test indicated that Cef did not alter locomotor activity or pain thresholds of mice (data not shown), which was consistent with previous reports (Miller et al, 2008;Rothstein et al, 2005). Thus, accelerated clearance of extracellular glutamate appears to underlie the ability of Cef to reverse the impairment of LTP and fear memory.…”

“…It is well known that Cef, one of the b-lactam antibiotics, increases expression and activity of GLT-1 (Rothstein et al, 2005). Previous studies have shown that single daily injection of Cef (200 mg/kg) for 5-7 days increases the GLT-1 expression and glutamate uptake in both the cortex and the striatum, as well as in the nucleus accumbens (Knackstedt et al, 2010;Miller et al, 2008;Sari et al, 2010). Therefore, the Cef-induced increase in GLT-1 expression has a direct effect on glutamate function.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Ceftriaxone attenuated paw clasping and improved motor flexibility (as measured in a plus maze test, and an open-field apparatus). As expected, ceftriaxone induced an increase in striatal GLT1 expression and consequently reversed the deficit in glutamate uptake characteristic of these mice (assessed by microdialysis) (Miller et al, 2008). Given these promising results, future studies should investigate whether ceftriaxone treatment (i.e., an increase in glutamate uptake by the glial cells) will also have a long-term effect on the behavior and neuropathology of R6/2 mice.…”

“…Thus, Miller et al (2008) have recently tested the effects of ceftriaxone, a betalactam antibiotic known to elevate GLT1 expression. Ceftriaxone was administered to symptomatic 6 week-old R6/2 mice and the animals were submitted to behavioral testing for 7 days after receiving the last drug injection.…”

Glutamate Transporter Activators as Anti-Nociceptive Agents

“…Pre-clinical studies performed thus far utilizing the rotarod, plus maze and open field locomotion tests demonstrated that GLT-1 up-regulation does not alter motor or cognitive function [18,33]. More sophisticated tests of motor, cognitive and neuronal function will be required.…”