Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model

Abstract

Huntington’s disease (HD) causes preferential loss of a subset of neurons in the brain although the huntingtin protein is expressed broadly in various neural cell types, including astrocytes. Glutamate-mediated excitotoxicity is thought to cause selective neuronal injury, and brain astrocytes have a central role in regulating extracellular glutamate. To determine whether full-length mutant huntingtin expression causes a cell-autonomous phenotype and perturbs astrocyte gliotransmitter release, we studied cultured cortical astrocytes from BACHD mice. Here, we report augmented glutamate release through Ca2+-dependent exocytosis from BACHD astrocytes. Although such release is usually dependent on cytosolic Ca2+ levels, surprisingly, we found that BACHD astrocytes displayed Ca2+ dynamics comparable to those in wild type astrocytes. These results point to a possible involvement of other factors in regulating Ca2+- dependent/vesicular release of glutamate from astrocytes. We found a biochemical footprint that would lead to increased availability of cytosolic glutamate in BACHD astrocytes: i) augmented de novo glutamate synthesis due to an increase in the level of the astrocyte specific mitochondrial enzyme pyruvate carboxylase; and ii) unaltered conversion of glutamate to glutamine, as there were no changes in the expression level of the astrocyte specific enzyme glutamine synthetase. This work identifies a new mechanism in astrocytes that could lead to increased levels of extracellular glutamate in HD and thus may contribute to excitotoxicity in this devastating disease.

Translational potential of astrocytes in brain disorders

“…Experimental increase in GLT-1 expression in astrocytes expressing mhtt by a lentiviral vector decreased astroglial reactivity (Faideau et al ., 2010), while treatment of R6/2 mice with ceftriaxone increased GLT-1 expression and improved motor symptoms (Faideau et al ., 2010). Astrocytes may also contribute to excitotoxicity in HD context through increased glutamate release, which indeed was found in astroglial cells isolated from the cortex of the BACHD mouse model (Lee et al ., 2013); this enhancement of glutamate release was linked to an increased expression of pyruvate carboxylate and hence an increased de novo production of glutamate. Besides compromised regulation of extracellular glutamate, astrocytes also display compromised potassium buffering, as recently demonstrated in HD mouse R6/2 and Q175 models (Tong et al, 2014).…”

Astroglial NMDA receptors inhibit expression of Kir4.1 channels in glutamate-overexposed astrocytes in vitro and in the brain of rats with acute liver failure

“…The onset of Huntington's disease (HD) symptoms in mouse was found to be causally related to decreased expression of Kir4.1 channel (Tong et al, 2014), and was associated with excessive Ca 2+ -dependent astrocytic Glu release (Lee et al, 2013). In this light, the role of astrocytic NMDA receptors in the development of HD deserves to be elucidated.…”

Astrocytes in Neurodegenerative Disease: Table 1.

“…The expression of polyQ-expanded htt by mouse striatal astrocytes was shown to impair glutamate transport (Faideau et al 2010), and enhanced calcium-dependent glutamate release has also been shown from astrocytes of an alternative mouse model of HD (Lee et al 2013b). The transport of other neurotransmitters may also be affected-the loss of astrocytic GABA release through GAT-3 has been implicated in reduced tonic inhibition in striatal output neurons from HD mice (Wojtowicz et al 2013).…”