Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity

TLDR

Huntington disease involves selective loss of striatal medium‑sized spiny neurons, and their vulnerability to glutamate excitotoxicity may depend on glial glutamate clearance, yet the contribution of glia remains poorly understood. Mutant huntingtin in glial cells reduces glutamate transporter expression and uptake, increasing neuronal vulnerability to excitotoxicity, indicating that impaired glial glutamate clearance contributes to HD pathology.

Abstract

Huntington disease (HD) is characterized by the preferential loss of striatal medium-sized spiny neurons (MSNs) in the brain. Because MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be largely influenced by the capacity of glial cells to remove extracellular glutamate. However, little is known about the role of glia in HD neuropathology. Here, we report that mutant huntingtin accumulates in glial nuclei in HD brains and decreases the expression of glutamate transporters. As a result, mutant huntingtin (htt) reduces glutamate uptake in cultured astrocytes and HD mouse brains. In a neuron–glia coculture system, wild-type glial cells protected neurons against mutant htt-mediated neurotoxicity, whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes decreased their protection of neurons against glutamate excitotoxicity. These findings suggest that decreased glutamate uptake caused by glial mutant htt may critically contribute to neuronal excitotoxicity in HD.