Regional alteration of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome)

Fiedler, Jenny L.; Epstein, Charles J.; Rapoport, Stanley I.; Caviedes, Raúl; Caviedes, Pablo

doi:10.1016/s0006-8993(09)90006-3

Cited by 36 publications

(50 citation statements)

References 30 publications

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“…This fact, added to other reports of slower depolarization of the action potential and depressed Na + currents in Ts16 hippocampal neurons and, conversely, enhanced depolarization in septal Ts16 neurons (Acevedo et al, 1995) are indications of a differential compromise of the central nervous system in the aneuploid condition and that different regions may be affected in qualitatively and quantitatively different manners, a possibility that also has been suggested in regards to differential compromise of cholinergic systems in the trisomic condition (Fiedler et al, 1994). The results presented here correlate well with previous findings suggesting that the higher gene dosage inherent to the trisomic condition affects neurons in different regions of the central nervous system in a differential fashion (Acevedo et al, 1995;Ault et al, 1989;Caviedes et al, 1990a;Galdzicki et al, 1993;Orozco et al, 1987Orozco et al, & 1988 and that this genetic imbalance could underlie impairments in neurotransmitter metabolism (Fiedler et al, 1994). Indeed, we speculate that excess dosage of genes due to triplication of murine chromosome 16 in the Ts16 condition affects the development of the cholinergic system in brain and spinal cord, reducing the number of cholinergic neurons in both tissues and differentially affecting the release of ACh under depolarizing conditions.…”

Section: Ca 2+ Currents In Trisomy 16 Neurons Have Slower Activation supporting

confidence: 51%

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Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down Syndrome)

Caviedes

Rapoport³

2006

Biol. Res.

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Down syndrome is determined by the presence of an extra copy of autosome 21 and is expressed by multiple abnormalities, with mental retardation being the most striking feature. The condition results in altered electrical membrane properties of fetal dorsal root ganglia (DRG) neurons, as in the trisomy 16 fetal mouse, an animal model of the human condition. Cultured trisomic DRG neurons from human and mouse fetuses present faster rates of depolarization and repolarization in the action potential compared to normal controls and a shorter spike duration. Also, trisomy 16 brain and spinal cord tissue exhibit reduced acetylcholine secretion. Therefore, we decided to study Ca 2+ currents in cultured DRG neurons from trisomy 16 and agematched control mice, using the whole-cell patch-clamp technique. Trisomic neurons exhibited a 62% reduction in Ca 2+ current amplitude and reduced voltage dependence of current activation at -30 and -20 mV levels. Also, trisomic neurons showed slower activation kinetics for Ca 2+ currents, with up to 80% increase in time constant values. Kinetics of the inactivation phase were similar in both conditions. The results indicate that murine trisomy 16 alter Ca 2+ currents, which may contribute to impaired cell function, including neurotransmitter release. These abnormalities also may alter neural development.

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Section: Ca 2+ Currents In Trisomy 16 Neurons Have Slower Activation supporting

confidence: 51%

“…Previously, we examined cholinergic function in brain and spinal cord tissue and in cultured neurons from Ts16 mouse compared with that of age-matched controls (Fiedler et al, 1994). Mean acetylcholinesterase (AChE) activity in both tissue types did not differ between trisomic and control conditions.…”

Section: Introductionmentioning

confidence: 99%

Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down Syndrome)

Caviedes

Rapoport³

2006

Biol. Res.

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“…Increased App expression disrupts NGF transport and causes cholinergic neuron degeneration (Salehi et al, 2006). In fact, Ts1Cje mice, which have a triplicated Mmu16 region without App triplication, do not show cholinergic system alterations (Chen et al, 2009), while in vitro studies in embryos from other models, carrying an extra copy of this gene, such as the Ts16 mouse (Fiedler et al, 1994;Opazo et al, 2006), present cholinergic deficits. Although the TS mouse carries an extra copy of the App gene, these mice do not develop amyloid plaques but display increased expression of full-length APP mRNA and APP protein in the cortex and hippocampus (Corrales et al, 2013;Seo and Isacson, 2005).…”

Section: Role Of Dyrk1a In Cholinergic Degeneration App and Aβmentioning

confidence: 97%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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“…The serotonergic, noradrenergic, GABAergic, and cholinergic systems are altered in trisomic mice and DS fetuses (Bar-Peled et al, 1991;Fiedler et al, 1994;Dierssen et al, 1997;Granholm et al, 2000;Kleschevnikov et al, 2004;Whittle et al, 2007) and although these alterations might be involved in neurogenesis impairment, the mechanisms underlying this defect are far from being elucidated. Consequently, no rational basis exists on which to devise therapeutic strategies aimed at improving neurogenesis in DS.…”

Section: Introductionmentioning

confidence: 99%

Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome

Bianchi¹,

Ciani²,

Guidi³

et al. 2010

Journal of Neuroscience

169

188

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Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampusdependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.

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Regional alteration of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome)

Cited by 36 publications

References 30 publications

Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down Syndrome)

Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down Syndrome)

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome

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