Exploring the contribution of astrocytes to Huntington disease

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Project Summary Huntington's disease (HD) is a fatal, progressive adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits. Degeneration of striatum medium spiny neurons (MSN) is the most prominent neuropathological change observed in HD. At present, there are no neuroprotective treatments for HD and symptomatic treatments are also largely ineffective. The mutated huntingtin (mHTT) protein is widely expressed in neuronal and non-neuronal cells, yet significant neurodegeneration is only observed for a subset of neurons in the brain. Understanding the toxicity produced by mHTT in a given cell type, the cellular interactions and underlying molecular changes in HD that contribute to the classic behavioral deficits and selective degeneration are likely to be critical in the design of effective therapies for the disease. One goal of this proposal is to expand our knowledge of the contribution of full length-mHTT (fl-mHTT) expressing astrocytes to deficits in striatal MSNs. Astrocytes are critical to the proper function and development of the nervous system. They modulate synaptic activity and neurotransmission. We have demonstrated that fl-mHTT expressing astrocytes in conditional fl-mHTT BACHD mice contribute to behavioral and neuropathological phenotypes observed in HD. Electrophysiological studies in BACHD mice revealed increased inhibitory input onto MSNs and a reduction of tonic inhibition in these neurons. There is increased spontaneous firing of striatal somatostatin GABAergic interneurons in the BACHD striatum. We found increased extracellular GABA (e[GABA]) in the striatum of 12 month old BACHD mice that is reduced with a decrease of mHTT expression in astrocytes. We also identified a decrease in GABA transporters, GAT1 and GAT3, which are responsible for uptake of e[GABA], in the striatum of the 12 month old BACHD mice. Recent studies revealed that astrocytes respond to activation of GABAergic somatostatin interneurons in the cortex through GAT3 and increases their inhibitory activity onto downstream pyramidal neurons. We hypothesize that deficits elicited by mHTT in somatostatin interneurons and astrocytes interact to contribute to the increased GABAergic inhibitory activity onto MSNs. We have designed experiments to assess the contribution of mHTT expressing astrocytes to the increased inhibition and reduced tonic conduction of MSNs. Furthermore, we will provide the first assessment of the role fl-mHTT expressing somatostatin interneurons play in the development of the electrophysiological changes in medium spiny neurons and the HD-like phenotypes in the BACHD mice. We will also assess whether overexpression of GABA transporters in the striatum decreases the electrophysiological deficits and e[GABA] observed in MSNs in the BACHD mice.