NMDA receptor function in mouse models of Huntington disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington disease (HD) is an autosomal dominant neurodegenerative disorder.
• Medium-sized spiny striatal neurons degenerate in HD.
• The HD gene and huntingtin protein functions are largely unknown.

Purpose of the Study:

• To investigate the role of N-methyl-D-aspartate (NMDA) receptors in Huntington disease.
• To examine NMDA receptor function in transgenic mouse models of HD.

Main Methods:

• Electrophysiological recordings of medium-sized striatal neurons in vitro.
• Application of NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonists.
• Immunohistochemistry to assess NMDA receptor subunit protein levels.

Main Results:

• Enhanced NMDA receptor-mediated currents and intracellular Ca(2+) flux in R6/2 and YAC72 HD mouse models.
• Reduced AMPA receptor currents in symptomatic R6/2 mice.
• Increased NMDA-R1 and decreased NMDA-R2A/B subunit proteins in R6/2 mice.

Conclusions:

• Alterations in NMDA receptor function may predispose striatal neurons to excitotoxic damage in HD.
• NMDA receptor dysfunction is implicated in the neuronal degeneration observed in Huntington disease.
• These findings highlight the functional importance of NMDA receptors in HD pathogenesis.