Neurochemical Changes in Murine Trisomy 16: Delay in Cholinergic and Catecholaminergic Systems

Abstract

Two strains of Mus musculus musculus, C57BL/6J and CD-1, and Mus musculus poschiavinus, the tobacco mouse, were used to study the effects of increased gene dosage of mouse chromosome 16 (MMU 16). A developmental delay has been found in the brains of murine trisomy 16 (Ts16) fetuses. Both the brain weight (in all three strains) and DNA content (in CD-1) were reduced, while protein content was unchanged in Ts16 compared to normal littermates. The daily increments of weight and protein (except in M. m. poschiavinus) were significantly greater in Ts16. The activities of choline acetyltransferase and acetylcholinesterase and muscarinic receptor binding were reduced. Their daily increments were also reduced to less than 56% that of littermates in Ts16 brains. The rate limiting enzymes of catecholaminergic neurons, tyrosine hydroxylase and dopamine beta-hydroxylase, and the concentration of catecholamines in the brains of Ts16 animals were lower. The activities of three other catecholaminergic enzymes, DOPA decarboxylase, catechol O-methyltransferase, and monoamine oxidase, were generally elevated in Ts16 brain, as were their daily increments. These observations indicate a significant developmental alteration in the maturation of the trisomic brain and suggest future avenues for defining the effect of increased gene dosage of MMU 16 in the CNS.

The human trisomy 21 brain: Insights from mouse models of Down syndrome

“…The mice are born after 20 days of gestation, and the period from E l 3 to 18 roughly corresponds to human fetal brain development between 18 and 33 weeks. As in Down syndrome, the brain of Ts 16 mice has a lower than normal weight, reduced cortical thickness, and hypocellularity in regions such as the cerebellum, the basal forebrain (including cholinergic neurons), and the locus ceruleus (noradrenergic neurons) (Ozand et al, 1984;Singer et al, 1984;Kiss et al, 1989). Alterations begin to appear at early stages of brain development, during neuronal proliferation and migration.…”

Adrenergic Sensitivity of Cultured Murine Trisomy 16 Cells

“…On the other hand, MMU 16 contains 2-2.5 times more of the cellular genetic material [3,7]; although it is known that the more distal segment of the MMU 16 contains the syntenic loci [7] its mapping is far from complete. Shared symptomatology of DS and murine Tsl6 is indi cated by retarded growth of the central nervous system [9,15], congenital heart disease [3] and other malformations [15]. Additionally, increased SOD-1 activity (1.35 fold) [8] has been observed in Tsl6 embryos.…”

“…Fetuses, 14-17 days old, were removed into a sterile petri dish and examined for morphological charac teristics of trisomy 16 (i.e., anasarca, open eye lids, etc. [9], They were then placed in sterile tubes containing Eagle's minimal essential medium (MEM). Normal littermates were treated similarity (controls).…”

“…The mice used in this work, both the controls and Tsl6 animals, were obtained as has been described elsewhere [9], The cAMP was determined using a standard radioimmu noassay kit purchased from New England Nuclear, Boston, Mass., USA. All reagents were purchased from Sigma Chemical Co., St. Louis, Mo., USA, except the phosphodiesterase inhibitor RO/20 (RO 20-1724 = 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone) [10] which was kindly provided by Dr. W.E.…”

Nerve growth factor corrects developmental impairments of basal forebrain cholinergic neurons in the trisomy 16 mouse.

“…Previous studies have demonstrated significant reductions in the developmental accrual of ChAT, the presynaptic marker of cholinergic neurons, in the brains of fetal Ts16 mice, as compared to their euploid littermates (11,12). Histochemical studies of the BF have revealed a significantly reduced complement of acetylcholinesterase (AChE)-positive presumptive cholinergic neurons in Ts16 fetuses (13,14).…”