Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF.
Huntington's disease (HD) is characterized by loss of striatal gamma-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 alpha1 subunit of GABA(A) 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.
Cepeda
Carlos
C
Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Starling
Amaal J
AJ
Wu
Nanping
N
Nguyen
Oanh K
OK
Uzgil
Besim
B
Soda
Takahiro
T
André
Veronique M
VM
Ariano
Marjorie A
MA
Levine
Michael S
MS
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D004195:Disease Models, Animal; D018756:GABA Antagonists; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid