RESUMEN
Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P(2)] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P(2) balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P(2) metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P(2) dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.
Asunto(s)
Trastornos del Conocimiento/enzimología , Síndrome de Down/enzimología , Homeostasis , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/patología , Modelos Animales de Enfermedad , Dosificación de Gen , Aprendizaje , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Monoéster Fosfórico Hidrolasas/genéticaRESUMEN
The Ts65Dn mouse shares many phenotypic characteristics of human Down syndrome. Here, we report that otitis media, characterized by effusion in the middle ear and hearing loss, was prevalent in Ts65Dn mice. Of the 53 Ts65Dn mice tested, 81.1% had high auditory-evoked brainstem response (ABR) thresholds for at least one of the stimulus frequencies (click, 8 kHz, 16 kHz and 32 kHz), in at least one ear. The ABR thresholds were variable and showed no tendency toward increase with age, from 2 to 7 months of age. Observation of pathology in mice, aged 3-4 months, revealed middle ear effusion in 11 of 15 Ts65Dn mice examined, but only in two of 11 wild-type mice. The effusion in each mouse varied substantially in volume and inflammatory cell content. The middle ear mucosae were generally thickened and goblet cells were distributed with higher density in the epithelium of the middle ear cavity of Ts65Dn mice as compared with those of wild-type controls. Bacteria of pathogenic importance to humans also were identified in the Ts65Dn mice. This is the first report of otitis media in the Ts65Dn mouse as a model characteristic of human Down syndrome.
Asunto(s)
Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Otitis Media con Derrame/complicaciones , Animales , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/microbiología , Síndrome de Down/genética , Síndrome de Down/fisiopatología , Oído Medio/patología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Pérdida Auditiva Conductiva/etiología , Pérdida Auditiva Conductiva/fisiopatología , Masculino , Ratones , Ratones Mutantes , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/microbiología , Otitis Media con Derrame/genética , Otitis Media con Derrame/patología , Otitis Media con Derrame/fisiopatología , Umbral Sensorial/fisiología , TrisomíaRESUMEN
Ts65Dn mouse is the most widely accepted model for Down syndrome. We previously showed that environmental enrichment improved spatial learning in female but deteriorated it in male Ts65Dn mice. This study analyzed the factors contributing to the disturbed cognition of male Ts65Dn mice after enriched housing, by allocating male control and Ts65Dn mice in four conditions after weaning: small (n = 2-3) and large group (n = 8-10) housing, and enriched housing in small (2-3) and large groups (8-10). Learning, aggressive behavior, anxiety-like behavior and biochemical correlates of stress were evaluated when Ts65Dn and control mice were 4-5 months old. Environmental enrichment in large mixed colonies of Ts65Dn and diploid littermates disturbed behavioral and learning skills of Ts65Dn mice in the Morris water maze. ACTH and testosterone levels were not modified in any group of mice. Ts65Dn and control mice subjected to enriched housing in large groups and Ts65Dn mice housed in large groups showed higher corticosterone levels. Aggressive behavior was evaluated by measuring the number of attacks performed in the presence of an intruder. Ts65Dn mice performed less attacks than controls in all conditions, especially after enriched housing, indicating subordination. In the plus maze, cognitive aspects (i.e. risk assessment) and motor components (open arm avoidance) of anxiety behavior were evaluated; no difference in any condition was found. It is suggested that an excess of social and/or physical stimulation in Ts65Dn mice may affect cognition by disturbing the emotional and behavioral components of the learning process.
Asunto(s)
Conducta Animal/fisiología , Cognición/fisiología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Ambiente , Hormona Adrenocorticotrópica/sangre , Agresión/fisiología , Análisis de Varianza , Animales , Corticosterona/sangre , Síndrome de Down/genética , Síndrome de Down/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Mutantes Neurológicos , Actividad Motora/fisiología , Tiempo de Reacción , Predominio Social , Natación , Testosterona/sangre , TrisomíaRESUMEN
The Ts65Dn mouse is a segmentally trisomic model for Down syndrome. Until now, Ts65Dn mice have been identified by the laborious methods of either chromosomal analysis of cultured peripheral lymphocytes or fluorescent in situ hybridization (FISH). We report here a quantitative PCR method for genotyping Ts65Dn mice, as well as a phenotypic description for visually preclassifying mice to be genotyped.
Asunto(s)
Algoritmos , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Perfilación de la Expresión Génica/métodos , Pruebas Genéticas/métodos , Reacción en Cadena de la Polimerasa/métodos , Animales , Modelos Animales de Enfermedad , Genotipo , Ratones , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
We have assessed the effects of enriched environment (EE) upon behavioral and cognitive performances of partially trisomic Ts65Dn (TS) mice and their control (CO) littermates. Enriched environment was applied to pups for 7 weeks after weaning. Circadian spontaneous activity (actimetry), exploratory behavior (hole board), activity in the open field and spatial memory (Morris Water Maze, repeated acquisition and cued paradigms) were analyzed in 86 female and 75 male mice, starting 15 days after completing enrichment. For each gender, mice were distributed in non-enriched and enriched control and trisomic groups. Enriched environment reduced in trisomic females and enhanced in trisomic males' circadian activity. Exploratory behavior was increased by enrichment in all groups, regardless of gender or presence of trisomy. In the Morris Water Maze, a significant improvement of the spatial memory was observed in enriched-control females, but not in enriched-control male mice, as assessed by distances traveled. Performances in the four groups of control animals were also consistently and significantly better than those of matching trisomic mice. In the acquisition trials, enrichment improved performance in trisomic female animals, but deteriorated in trisomic male mice. In all groups, changes in escape latencies and distances induced by enrichment were accounted for by changes in the total time spent in the periphery of the pool, indicating changes in learning strategy. Working memory was the function more affected by enrichment. It is concluded that enriched environment induces behavioral and learning changes in trisomic mice, although gender plays a significant modulatory role.
Asunto(s)
Conducta Animal/fisiología , Síndrome de Down/psicología , Ambiente , Aprendizaje/fisiología , Animales , Ritmo Circadiano/fisiología , Señales (Psicología) , Femenino , Masculino , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Actividad Motora/fisiología , Caracteres SexualesRESUMEN
The Ts65Dn mouse is the most studied and complete aneuploid model of Down syndrome (DS) widely available. As a model for human trisomy 21, these mice display many attractive features, including performance deficits in different behavioral tasks, alterations in synaptic plasticity and adult neurogenesis, motor dysfunction, and age-dependent cholinergic neurodegeneration. Currently, Ts65Dn mice are maintained on a genetic background that leads to blindness in about 25% of their offspring, because it segregates for the retinal degeneration 1 (Pde6b(rd1)) mutation of C3H/HeSnJ. This means that 25% of the mice have to be discarded in most experiments involving these animals, which is particularly problematic because the Ts65Dn stock has low reproductive performance. To circumvent this problem, we have bred the Ts65Dn extra chromosome many generations into a closely related genetic background that does not carry the Pde6b(rd1) mutation. Although the new genetic background is expected to be nearly identical to the original, differences in genetic background have the potential to alter mouse performance in certain behavioral tests. Therefore, we designed the present study primarily as a behavioral validation of Ts65Dn mice of the new background. We compared side-by-side their performance with that of Ts65Dn mice of the original background on the following set of assessments: (1) body length and weight; (2) 24-h locomotor activity; (3) the Morris water maze; (4) fear conditioning; and (5) grip strength. Except for very subtle differences on water maze performance, we found no significant differences between Ts65Dn mice on the two backgrounds in the measures assessed.
Asunto(s)
Conducta Animal/fisiología , Síndrome de Down/genética , Fenotipo , Análisis de Varianza , Animales , Tamaño Corporal/genética , Peso Corporal/genética , Condicionamiento Clásico/fisiología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Conducta Exploratoria/fisiología , Miedo , Fuerza de la Mano/fisiología , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/genética , Conducta Espacial/fisiologíaRESUMEN
PURPOSE: The Ts65Dn mouse is the most complete widely available animal model of Down syndrome (DS). Quantitative information was generated about visual function in the Ts65Dn mouse by investigating their visual capabilities by means of electroretinography (ERG) and patterned visual evoked potentials (pVEPs). METHODS: pVEPs were recorded directly from specific regions of the binocular visual cortex of anesthetized mice in response to horizontal sinusoidal gratings of different spatial frequency, contrast, and luminance generated by a specialized video card and presented on a 21-in. computer display suitably linearized by gamma correction. RESULTS: ERG assessments indicated no significant deficit in retinal physiology in Ts65Dn mice compared with euploid control mice. The Ts65Dn mice were found to exhibit deficits in luminance threshold, spatial resolution, and contrast threshold, compared with the euploid control mice. The behavioral counterparts of these parameters are luminance sensitivity, visual acuity, and the inverse of contrast sensitivity, respectively. CONCLUSIONS: DS includes various phenotypes associated with the visual system, including deficits in visual acuity, accommodation, and contrast sensitivity. The present study provides electrophysiological evidence of visual deficits in Ts65Dn mice that are similar to those reported in persons with DS. These findings strengthen the role of the Ts65Dn mouse as a model for DS. Also, given the historical assumption of integrity of the visual system in most behavioral assessments of Ts65Dn mice, such as the hidden-platform component of the Morris water maze, the visual deficits described herein may represent a significant confounding factor in the interpretation of results from such experiments.
Asunto(s)
Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Potenciales Evocados Visuales/fisiología , Retina/fisiopatología , Trastornos de la Visión/fisiopatología , Animales , Sensibilidad de Contraste/fisiología , Cruzamientos Genéticos , Electrorretinografía , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Umbral Sensorial , Percepción Espacial/fisiología , Agudeza Visual/fisiología , Corteza Visual/fisiologíaRESUMEN
Ts65Dn and littermate controls were trained to respond (nose-poke) under operant schedules of reinforcement. A small difference was observed in the initial operant training of the Ts65Dn mouse that disappeared with training under a fixed-ratio 15 schedule of milk presentation. No difference was observed in a position reversal task in which mice initially trained to respond upon one photocell had to learn to respond on a previously inactive photocell. Under an incremental repeated acquisition of behavioral chains schedule, no difference was observed when one or two responses were required to complete the sequence. However, when three or four responses were required to complete the sequence, a marked deficit was observed in the Ts65Dn mice. These results show that both Ts65Dn and littermate controls can be trained to respond under operant schedules of reinforcement, but that Ts65Dn mice have a learning deficit that is correlated with task difficulty.