Differential effects of SNARE-dependent gliotransmission on behavioral phenotypes in a mouse model of Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the widely expressed huntingtin protein. Multiple studies have indicated the importance of mutant huntingtin (mHTT) in astrocytes to HD pathogenesis. Astrocytes exhibit SNARE-dependent exocytosis and gliotransmission, which can be hampered by transgenic expression of dominant negative SNARE (dnSNARE) in these glial cells. We used BACHD mice and crossed them with the dnSNARE model to determine if pan-astrocytic SNARE-dependent exocytosis plays an important role in vivo in the progression of HD behavioral phenotypes. We assessed motor and neuropsychiatric behaviors in these mice. At 12 months of age there was a significant improvement in motor coordination (rotarod test) in BACHD/dnSNARE mice when compared to BACHD mice. Analyses of open field performance revealed significant worsening of center entry (at 9 and 12 months), but not distance traveled in BACHD/dnSNARE when compared to BACHD mice, and variable/inconclusive results on vertical plane entry. While no differences between BACHD and BACHD/dnSNARE mice at 12 months of age in the forced swim test were found, we did observe a significant decrease in performance of BACHD/dnSNARE mice in the light-dark box paradigm. Thus, reduction of astrocytic SNARE-dependent exocytosis has differential effects on the psychiatric-like and motor phenotypes observed in BACHD mice. These data suggest broadly targeting SNARE-dependent exocytosis in astrocytes throughout the brain as a means to modulate gliotransmission in HD may contribute to worsening of specific behavioral deficits and perhaps a brain-region specific approach would be required.

Mutant huntingtin reduction in astrocytes slows disease progression in the BACHD conditional Huntington's disease mouse model.

Neuronal and non-neuronal cells express the huntingtin (HTT) protein, yet neurodegeneration in Huntington's disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length human mutant HTT (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis. To directly assess the necessity of fl-mHTT in astrocytes for HD pathogenesis, we used a mouse genetic approach and bred the conditional mHTT-expressing BACHD mouse model with GFAP-CreERT2 mice. We show that GFAP-CreERT2 expression in these mice is highly selective for astrocytes, and we are able to significantly reduce the expression of fl-mHTT protein in the striatum and cortex of BACHD/GFAP-CreERT2-tam mice. We performed behavioral, electrophysiological and neuropathological analyses of BACHD and BACHD/GFAP-CreERT2-tam mice. Behavioral analyses of BACHD/GFAP-CreERT2-tam mice demonstrate significant improvements in motor and psychiatric-like phenotypes. We observe improvements in neuropathological and electrophysiological phenotypes in BACHD/GFAP-CreERT2-tam mice compared to BACHD mice. We observed a restoration of the normal level αB-crystallin in the striatum of the BACHD/GFAP-CreERT2 mice, indicating a cell autonomous effect of mHTT on its expression. Taken together, this work indicates that astrocytes are important contributors to the progression of the behavioral and neuropathological phenotypes observed in HD.