ABSTRACT
BACKGROUND: Down's syndrome (DS) is caused by triplication of all or part of human chromosome 21 and is characterized by a decrease in the overall size of the brain. One of the brain regions most affected is the cerebellum, in which the number of granule cells (GCs) is markedly decreased. GCs process sensory information entering the cerebellum via mossy fibres and pass it on to Purkinje cells and inhibitory interneurons. How GCs transform incoming signals depends on their input-output relationship, which is adjusted by tonically active GABA(A) receptor channels. RESULTS: We report that in the Ts65Dn mouse model of DS, in which cerebellar volume and GC number are decreased as in DS, the tonic GABA(A) receptor current in GCs is smaller than in wild-type mice and is less effective in moderating input resistance and raising the minimum current required for action potential firing. We also find that tonically active GABA(A) receptors curb the height and broaden the width of action potentials in wild-type GCs but not in Ts65Dn GCs. Single-cell real-time quantitative PCR reveals that these electrical differences are accompanied by decreased expression of the gene encoding the GABA(A) receptor ß3 subunit but not genes coding for some of the other GABA(A) receptor subunits expressed in GCs (α1, α6, ß2 and δ). CONCLUSIONS: Weaker moderation of excitability and action potential waveform in GCs of the Ts65Dn mouse by tonically active GABA(A) receptors is likely to contribute to atypical transfer of information through the cerebellum. Similar changes may occur in DS.
