ALTERATIONS OF CENTRAL NORADRENERGIC TRANSMISSION IN TS65DN MOUSE, A MODEL FOR DOWN-SYNDROME

Mice with segmental trisomy 16 (Ts65Dn) which have triplication of a r egion of mouse chromosome 16 homologous to the Down syndrome critical region in human chromosome 21, are used as a model for Down syndrome. Functioning of the central beta-noradrenergic transmission was studied in Ts65Dn mice. Binding analysis in cerebral cortex revealed no chang e in the number of beta-adrenoceptors and a slight reduction of affini ty. The beta-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex un der basal conditions and after stimulation with isoprenaline and forsk olin. Basal production of cAMP was significantly reduced in hippocampu s and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAM P accumulation were similar in both groups of mice, Stimulation of cAM P production by isoprenaline (10 mu M) and forskolin (10 mu M) was muc h higher in hippocampus than in cerebral cortex of either group. In bo th areas, but not in cerebellum, the stimulatory responses were consis tently and significantly smaller in Ts65Dn than in control mice. Conce ntration-response curves for isoprenaline and forskolin were, generate d in the cerebral cortex. E(max) responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response cu rve to isoprenaline was markedly depressed whereas that to forskolin w as similar to control. It is concluded that Ts65Dn mice show seven def iciencies in the synaptic transmission of the central beta-noradrenerg ic system, which are selective for specific brain areas. (C) 1997 Else vier Science B.V.