In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects

Abstract

Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.

Astrogliosis

“…From a different perspective, expression and function of the glutamate transporter GLT-1 can be modulated up or down during astrogliosis depending on the nature of the insult and time after the insult, and this regulation can impact outcome by influencing extracellular glutamate levels and the potential for neuronal excitotoxicity (Bianchi et al 2013). The mTORAkt-NF-kB pathway is one molecular signaling mechanism that can modulate astrocyte expression of Glt-1 (Pawlak et al 2005;Faideau et al 2010;Ji et al 2013). Findings such as these support a model in which many different specific signaling mechanisms can trigger different specific molecular, morphological, and functional changes in reactive astrocytes.…”

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

“…On the membranes of astrocytes, which are the major subtype of glial cells, there are two types of glutamate transporters (GLT-1 and GLAST) that do most of the work in clearing extracellular excitatory neurotransmitters [7,8] . It has been shown that small fragments of N-terminal mutant Htt (such as N-208, N-171), which were reported to be more pathogenic than full-length mutant Htt, caused decreased expression of GLT-1 [2,5] .…”

Early Dysfunction of Neural Transmission and Cognitive Processing in Huntington’s Disease

“…Energy is required for astrocytes to accomplish GLU transport (Azarias et al, 2011), and a corresponding decline in the astrocytic expression of GLU transporters seems to reach a point where the striatum can no longer keep up with the behavior-related surges of GLU necessary to generate striatal bursting activity (Wilson, 2004). It seems this occurs despite observations that astrocytes initially proliferate in HD, perhaps as a compensatory strategy (Faideau et al, 2010). It is also relevant to pre-HD that developmental changes seem to take place between youth and later adulthood regarding astrocytic participation in GLU clearance.…”