Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF.
J Neurosci Res
; 78(6): 855-67, 2004 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-15505789
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Huntington
/
Fator Neurotrófico Derivado do Encéfalo
/
Ácido gama-Aminobutírico
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Neurosci Res
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Estados Unidos