Presynaptic GABA A receptors control integration of nicotinic input onto dopaminergic axons in the striatum.

Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABA A Rs) and nicotinic acetylcholine receptors (nAChRs) which are both independently positioned to shape striatal dopamine release. Using electrophysiology and calcium imaging, we investigated how interactions between GABA A Rs and nAChRs influence dopaminergic axon excitability. Direct axonal recordings showed that benzodiazepine application suppresses subthreshold axonal input from cholinergic interneurons (CINs). In imaging experiments, we used the first temporal derivative of presynaptic calcium signals to distinguish between direct- and nAChR-evoked activity in dopaminergic axons. We found that GABA A R antagonism with gabazine selectively enhanced nAChR-evoked axonal signals. Acetylcholine release was unchanged in gabazine suggesting that GABA A Rs located on dopaminergic axons, but not CINs, mediated this enhancement. Unexpectedly, we found that a widely used GABA A R antagonist, picrotoxin, inhibits axonal nAChRs and should be used cautiously for striatal circuit analysis. Overall, we demonstrate that GABA A Rs on dopaminergic axons regulate integration of nicotinic input to shape presynaptic excitability.

CAG Repeat Instability in the Peripheral and Central Nervous System of Transgenic Huntington's Disease Monkeys.

Huntington's Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats has been well-documented, the underlying mechanisms had not been fully delineated. Increased CAG repeat length is associated with a more severe phenotype, greater TNR instability, and earlier age of onset. The direct relationship between CAG repeat length and molecular pathogenesis makes TNR instability a useful measure of symptom severity and tissue susceptibility. Thus, we examined the tissue-specific TNR instability of transgenic nonhuman primate models of Huntington's disease. Our data show a similar profile of CAG repeat expansion in both rHD1 and rHD7, where high instability was observed in testis, liver, caudate, and putamen. CAG repeat expansion was observed in all tissue samples, and tissue- and CAG repeat size-dependent expansion was observed. Correlation analysis of CAG repeat expansion and the gene expression profile of four genes in different tissues, clusterin (CLU), transferrin (TF), ribosomal protein lateral stalk subunit P1 (RPLP1), and ribosomal protein L13a (RPL13A), showed a strong correlation with CAG repeat instability. Overall, our data, along with previously published studies, can be used for studying the biology of CAG repeat instability and identifying new therapeutic targets.

Progressive Polyglutamine Repeat Expansion in Peripheral Blood Cells and Sperm of Transgenic Huntington's Disease Monkeys.

The expanded CAG repeat results in somatic mosaicism and genetic anticipation in Huntington's disease (HD). Here we report a longitudinal study examining CAG repeat instability in lymphocytes and sperm of three HD monkeys throughout their whole life-span that encompass the prodromal to symptomatic stages of HD. We demonstrate a progressive increase in CAG repeat length in lymphocytes and sperm as the animals aged. We also examined the impact of CAG repeat length on expansion rate, which showed a clear linear correlation up to 62Q, and high instability after. Our findings stress the importance of further investigation in CAG instability in peripheral blood cells longitudinally.