Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome.
Mice with segmental trisomy 16 (Ts65Dn) which have triplication of a region 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 change in the number of beta-adrenoceptors and a slight reduction of affinity. The beta-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex under basal conditions and after stimulation with isoprenaline and forskolin. Basal production of cAMP was significantly reduced in hippocampus and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAMP accumulation were similar in both groups of mice. Stimulation of cAMP production by isoprenaline (10 microM) and forskolin (10 microM) was much higher in hippocampus than in cerebral cortex of either group. In both areas, but not in cerebellum, the stimulatory responses were consistently and significantly smaller in Ts65Dn than in control mice. Concentration-response curves for isoprenaline and forskolin were generated in the cerebral cortex. Emax responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response curve to isoprenaline was markedly depressed whereas that to forskolin was similar to control. It is concluded that Ts65Dn mice show severe deficiencies in the synaptic transmission of the central beta-noradrenergic system, which are selective for specific brain areas.
Dierssen
M
M
Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
Vallina
I F
IF
Baamonde
C
C
García-Calatayud
S
S
Lumbreras
M A
MA
Flórez
J
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D009638:Norepinephrine / Q000494:pharmacology; D009928:Organ Specificity; D011412:Propanolamines / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000242:Cyclic AMP; D007545:Isoproterenol; C033394:CGP 12177; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine