Increased GABAergic function in mouse models of Huntington's disease: Reversal by BDNF

Carlos Cepeda, Amaal J. Starling, Nanping Wu, Oanh K. Nguyen, Besim Uzgil, Takahiro Soda, Veronique M. André, Marjorie A. Ariano, Michael S. Levine

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


Huntington's disease (HD) is characterized by loss of striatal γ-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous α1 subunit of GABAA receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.

Original languageEnglish (US)
Pages (from-to)855-867
Number of pages13
JournalJournal of Neuroscience Research
Issue number6
StatePublished - Dec 15 2004


  • BDNF
  • Electrophysiology
  • GABA receptor
  • R6/2
  • Synaptic currents

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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