The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

Anton Reiner, D. C. Lafferty, H. B. Wang, N. Del Mar, Yunping Deng

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Abstract

Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Since corticostriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120-125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20. mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10. weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15-20% cortical and striatal neuron loss, normalization of SP striatal neuron neurochemistry, and to a lesser extent enkephalinergic striatal neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP striatal neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD.

Original languageEnglish (US)
Pages (from-to)75-91
Number of pages17
JournalNeurobiology of Disease
Volume47
Issue number1
DOIs
StatePublished - Jul 1 2012

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LY 379268
Excitatory Amino Acid Agonists
Huntington Disease
Corpus Striatum
Neurochemistry
Neurons
Maximum Tolerated Dose
Glutamic Acid
Autoreceptors
Aptitude
Subcutaneous Injections
Gait
Phenotype
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Neurology

Cite this

The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice. / Reiner, Anton; Lafferty, D. C.; Wang, H. B.; Del Mar, N.; Deng, Yunping.

In: Neurobiology of Disease, Vol. 47, No. 1, 01.07.2012, p. 75-91.

Research output: Contribution to journalArticle

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