RESUMO
Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.
Assuntos
Síndrome de Down , Células de Lugar , Animais , Modelos Animais de Doenças , Ritmo Gama , Hipocampo , Masculino , CamundongosRESUMO
Down syndrome (DS) or Trisomy 21 is the most common genetic cause of mental retardation with severe learning and memory deficits. DS is due to the complete or partial triplication of human chromosome 21 (HSA21) triggering gene overexpression and protein synthesis alterations responsible for a plethora of mental and physical phenotypes. Among the diverse brain target systems that affect hippocampal-dependent learning and memory deficit impairments in DS, the upregulation of the endocannabinoid system (ECS), and notably the overexpression of the cannabinoid type-1 receptor (CB1), seems to play a major role. Combining various protein and gene expression targeted approaches using western blot, qRT-PCR and FISH techniques, we investigated the expression pattern of ECS components in the hippocampus (HPC) of male Ts65Dn mice. Among all the molecules that constitute the ECS, we found that the expression of the CB1 is altered in the HPC of Ts65Dn mice. CB1 distribution is differentially segregated between the dorsal and ventral part of the HPC and within the different cell populations that compose the HPC. CB1 expression is upregulated in GABAergic neurons of Ts65Dn mice whereas it is downregulated in glutamatergic neurons. These results highlight a complex regulation of the CB1 encoding gene (Cnr1) in Ts65Dn mice that could open new therapeutic solutions for this syndrome.
Assuntos
Canabinoides , Síndrome de Down , Animais , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismoRESUMO
Stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to improve cognitive impairment due to intellectual disability, aging, and neurodegeneration, however the underlying neural mechanisms are poorly understood. We investigated the neural correlates of memory amelioration produced by postnatal environmental enrichment (EE) in diploid mice and the Ts65Dn mouse model of Down syndrome (trisomy 21). We recorded neural activities in brain structures key for memory processing, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in non-enriched or enriched environments. Enriched wild-type animals exhibited enhanced neural synchrony in the hippocampus across different brain states (increased gamma oscillations, theta-gamma coupling, sleep ripples). Trisomic females showed increased theta and gamma rhythms in the hippocampus and prefrontal cortex across different brain states along with enlarged ripples and disrupted circuit gamma signals that were associated with memory deficits. These pathological activities were attenuated in their trisomic EE-reared peers. Our results suggest distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE and put forward hippocampal-prefrontal hypersynchrony and miscommunication as major targets underlying the beneficial effects of EE in intellectual disability.
Assuntos
Síndrome de Down , Deficiência Intelectual , Animais , Feminino , Ritmo Gama , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-FrontalRESUMO
Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the life span have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains, we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice, we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice, the distalmost apical branches were missing or reduced in number, but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.
Assuntos
Síndrome de Down , Neocórtex , Animais , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese , Células Piramidais/patologiaRESUMO
Down syndrome (DS) induces a variable phenotype including intellectual disabilities and early development of Alzheimer's disease (AD). Moreover, individuals with DS display accelerated aging that affects diverse organs, among them the brain. The Ts65Dn mouse is the most widely used model to study DS. Progressive loss of cholinergic neurons is one of the hallmarks of AD present in DS and in the Ts65Dn model. In this study, we quantify the number of cholinergic neurons in control and Ts65Dn mice, observing a general reduction in their number with age but in particular, a greater loss in old Ts65Dn mice. Increased expression of the m1 muscarinic receptor in the hippocampus counteracts this loss. Cholinergic neurons in the Ts65Dn mice display overexpression of the early expression gene c-fos and an increase in the expression of ß-galactosidase, a marker of senescence. A possible mechanism for senescence induction could be phosphorylation of the transcription factor FOXO1 and its retention in the cytoplasm, which we are able to confirm in the Ts65Dn model. In our study, using Ts65Dn mice, we observe increased cholinergic activity, which induces a process of early senescence that culminates in the loss of these neurons.
Assuntos
Doença de Alzheimer , Síndrome de Down , Doença de Alzheimer/metabolismo , Animais , Colinérgicos , Modelos Animais de Doenças , Camundongos , Camundongos TransgênicosRESUMO
OBJECTIVES: The brains of individuals with Down syndrome (DS) present defects in neurogenesis and synaptogenesis during prenatal and early postnatal stages that are partially responsible for their cognitive disabilities. Because oleic and linolenic fatty acids enhance neurogenesis, synaptogenesis, and cognitive abilities in rodents and humans, in this study we evaluated the ability of these compounds to restore these altered phenotypes in the Ts65Dn (TS) mouse model of DS during early postnatal stages. METHODS: TS and euploid mice were treated with oleic or linolenic acid from PD3 to PD15, and the short- and long- term effects of these acids on neurogenesis and synaptogenesis were evaluated. The effects of these treatments on the cognitive abilities of TS mice during early adulthood were also evaluated. RESULTS: Administration of oleic or linolenic acid did not modify cell proliferation immediately after treatment discontinuation or several weeks later. However, oleic acid increased the total number of DAPI+ cells (+ 26%), the percentage of BrdU+ cells that acquired a neural phenotype (+ 9.1%), the number of pre- (+ 29%) and post-synaptic (+ 32%) terminals and the cognitive abilities of TS mice (+ 18.1%). In contrast, linolenic acid only produced a slight cognitive improvement in TS mice. (+12.1%). DISCUSSION: These results suggest that early postnatal administration of oleic acid could palliate the cognitive deficits of DS individuals.
Assuntos
Síndrome de Down , Animais , Cognição , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/terapia , Feminino , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ácido Oleico , Gravidez , Ácido alfa-Linolênico/uso terapêuticoRESUMO
Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus-dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi-stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.
Assuntos
Síndrome de Down , Animais , Modelos Animais de Doenças , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NeurogêneseRESUMO
OBJECTIVE: Recent clinical trials targeting amyloid beta (Aß) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. BACKGROUND: AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein-coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C-terminal fragment (C99, also known as ß-CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. NEW/UPDATED HYPOTHESIS: We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full-length APP (fl-APP) and its products, including ß-CTF and possibly Aß peptides (Aß42 and Aß40), drive AD pathogenesis through an endosome-dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl-APP. In vitro, Posiphen lowered fl-APP and its C-terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl-APP, C-terminal fragments and small reductions in Aß species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p-tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal-regulated kinase), and CREB (cAMP response element-binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. MAJOR CHALLENGES FOR THE HYPOTHESIS: Important unanswered questions are: (1) When should one intervene in those with DS; (2) would an APP-based strategy have untoward consequences on possible adaptive changes induced by chronically increased APP gene dose; (3) do other genes present on chromosome 21, or on other chromosomes whose expression is dysregulated in DS, contribute to AD pathogenesis; and (4) can one model strategies that combine the use of an APP-based treatment with those directed at other AD phenotypes including p-tau and inflammation. LINKAGE TO OTHER MAJOR THEORIES: The APP gene dose hypothesis interfaces with the amyloid cascade hypothesis of AD as well as with the genetic and cell biological observations that support it. Moreover, upregulation of fl-APP protein and products may drive downstream events that dysregulate tau homeostasis and inflammatory responses that contribute to propagation of AD pathogenesis.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Inibidores da Colinesterase/administração & dosagem , Síndrome de Down/genética , Endossomos , Fenótipo , Fisostigmina/análogos & derivados , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Endossomos/metabolismo , Endossomos/patologia , Humanos , Camundongos , Neurônios/metabolismo , Fosforilação , Fisostigmina/administração & dosagemRESUMO
Down syndrome (DS) or trisomy of chromosome 21 (Hsa21) is characterized by impaired hippocampal-dependent learning and memory. These alterations are due to defective neurogenesis and to neuromorphological and functional anomalies of numerous neuronal populations, including hippocampal granular cells (GCs). It has been proposed that the additional gene dose in trisomic cells induces modifications in nuclear compartments and on the chromatin landscape, which could contribute to some DS phenotypes. The Ts65Dn (TS) mouse model of DS carries a triplication of 92 genes orthologous to those found in Hsa21, and shares many phenotypes with DS individuals, including cognitive and neuromorphological alterations. Considering its essential role in hippocampal memory formation, we investigated whether the triplication of this set of Hsa21 orthologous genes in TS mice modifies the nuclear architecture of their GCs. Our results show that the TS mouse presents alterations in the nuclear architecture of its GCs, affecting nuclear compartments involved in transcription and pre-rRNA and pre-mRNA processing. In particular, the GCs of the TS mouse show alterations in the nucleolar fusion pattern and the molecular assembly of Cajal bodies (CBs). Furthermore, hippocampal GCs of TS mice present an epigenetic dysregulation of chromatin that results in an increased heterochromatinization and reduced global transcriptional activity. These nuclear alterations could play an important role in the neuromorphological and/or functional alterations of the hippocampal GCs implicated in the cognitive dysfunction characteristic of TS mice.
Assuntos
Cromatina/genética , Síndrome de Down/genética , Hipocampo/metabolismo , Neurônios/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Cognição/fisiologia , Corpos Enovelados/genética , Corpos Enovelados/metabolismo , Modelos Animais de Doenças , Síndrome de Down/patologia , Hipocampo/patologia , Humanos , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Neurogênese/genética , Neurogênese/fisiologia , Neurônios/patologiaRESUMO
Inflammation can be resolved by pro-homeostatic lipids called specialized pro-resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle-aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro-inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age-matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Síndrome de Down/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Hipocampo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Doença de Alzheimer/patologia , Animais , Síndrome de Down/patologia , Ácido Eicosapentaenoico/farmacologia , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos TransgênicosRESUMO
Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drug screening campaign showed that the ß2-adrenergic receptor (ß2-AR) agonists clenbuterol hydrochloride (CLEN) and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dn model of DS. The goal of the current study was to establish their efficacy in vivo, in the Ts65Dn model. We found that, at variance with the in vitro experiments, treatment with CLEN or SALM did not restore neurogenesis in the hippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLEN or SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells were restored and the lowest dose tested here (0.01â¯mg/kg/day) was sufficient to elicit these effects. CLEN and SALM are used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study suggests that treatment with these ß2-AR agonists may be a therapy of choice in order to correct dendritic development in DS but is not suitable to rescue neurogenesis.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Clembuterol/uso terapêutico , Giro Denteado/efeitos dos fármacos , Síndrome de Down/tratamento farmacológico , Xinafoato de Salmeterol/uso terapêutico , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacosRESUMO
BACKGROUND: The cognitive dysfunction in Down syndrome (DS) is partially caused by deficient neurogenesis during fetal stages. Curcumin enhances neurogenesis and learning and memory. OBJECTIVES: We aimed to test the ability of curcumin to rescue the neuromorphological and cognitive alterations of the Ts65Dn (TS) mouse model of DS when administered prenatally or during early postnatal stages, and to evaluate whether these effects were maintained several weeks after the treatment. METHODS: To evaluate the effects of prenatal curcumin administration, 65 pregnant TS females were subcutaneously treated with curcumin (300 mg/kg) or vehicle from ED (Embryonic Day) 10 to PD (Postnatal Day) 2. All the analyses were performed on their TS and Control (CO) male and female progeny. At PD2, the changes in neurogenesis, cellularity, and brain weight were analyzed in 30 TS and CO pups. The long-term effects of prenatal curcumin were evaluated in another cohort of 44 TS and CO mice between PD30 and PD45. The neuromorphological effects of the early postnatal administration of curcumin were assessed on PD15 in 30 male and female TS and CO pups treated with curcumin (300 mg/kg) or vehicle from PD2 to PD15. The long-term neuromorphological and cognitive effects were assessed from PD60 to PD90 in 45 mice. Data was compared by ANOVAs. RESULTS: Prenatal administration of curcumin increased the brain weight (+45%, P < 0.001), the density of BrdU (bromodeoxyuridine)- (+150%, P < 0.001) and DAPI (4',6-diamidino-2-phenylindole)- (+38%, P = 0.005) positive cells, and produced a long-term improvement of cognition in TS (+35%, P = 0.007) mice with respect to vehicle-treated mice. Postnatal administration of curcumin did not rescue any of the short- or long-term altered phenotypes of TS mice. CONCLUSION: The beneficial effects of prenatal curcumin administration to TS mice suggest that it could be a therapeutic strategy to treat DS cognitive disabilities.
Assuntos
Encéfalo/crescimento & desenvolvimento , Cognição/efeitos dos fármacos , Curcumina/farmacologia , Síndrome de Down/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Ração Animal/análise , Animais , Encéfalo/efeitos dos fármacos , Curcumina/administração & dosagem , Dieta/veterinária , Esquema de Medicação , Feminino , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Transgênicos , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
BACKGROUND: The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus, enhancing prenatal neurogenesis in DS could prevent or reduce some of the neuromorphological and cognitive defects found in postnatal stages. OBJECTIVES: As fatty acids play a fundamental role in morphogenesis and brain development during fetal stages, in this study, we aimed to enhance neurogenesis and the cognitive abilities of the Ts65Dn (TS) mouse model of DS by administering oleic or linolenic acid. METHODS: In total, 85 pregnant TS females were subcutaneously treated from Embryonic Day (ED) 10 until Postnatal Day (PD) 2 with oleic acid (400 mg/kg), linolenic acid (500 mg/kg), or vehicle. All analyses were performed on their TS and Control (CO) male and female progeny. At PD2, we evaluated the short-term effects of the treatments on neurogenesis, cellularity, and brain weight, in 40 TS and CO pups. A total of 69 TS and CO mice were used to test the long-term effects of the prenatal treatments on cognition from PD30 to PD45, and on neurogenesis, cellularity, and synaptic markers, at PD45. Data were compared by ANOVAs. RESULTS: Prenatal administration of oleic or linolenic acid increased the brain weight (+36.7% and +45%, P < 0.01), the density of BrdU (bromodeoxyuridine)- (+80% and +115%; P < 0.01), and DAPI (4',6-diamidino-2-phenylindole)-positive cells (+64% and +22%, P < 0.05) of PD2 TS mice with respect to the vehicle-treated TS mice. Between PD30 and PD45, TS mice prenatally treated with oleic or linolenic acid showed better cognitive abilities (+28% and +25%, P < 0.01) and a higher density of the postsynaptic marker PSD95 (postsynaptic density protein 95) (+65% and +44%, P < 0.05) than the vehicle-treated TS animals. CONCLUSION: The beneficial cognitive and neuromorphological effects induced by oleic or linolenic acid in TS mice suggest that they could be promising pharmacotherapies for DS-associated cognitive deficits.
Assuntos
Síndrome de Down/fisiopatologia , Exposição Materna , Ácido Oleico/administração & dosagem , Ácido alfa-Linolênico/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Síndrome de Down/patologia , Feminino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Ácido Oleico/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ácido alfa-Linolênico/farmacologiaRESUMO
Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-ß (Aß) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aß1-11 fragment, in ameliorating Aß-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aß1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aß from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities. Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aß from a young age by slowing the progression of dementia.
Assuntos
Peptídeos beta-Amiloides/imunologia , Síndrome de Down/imunologia , Síndrome de Down/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/metabolismo , DNA/imunologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Imunização/métodos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microglia/metabolismo , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas tau , Quinases DyrkRESUMO
Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivoSIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.
Assuntos
Síndrome de Down/fisiopatologia , Condutos Olfatórios/fisiopatologia , Olfato , Visão Ocular , Vias Visuais/fisiopatologia , Animais , Cegueira/fisiopatologia , Proteínas do Citoesqueleto/genética , Dominância Ocular , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Córtex Visual/fisiopatologiaRESUMO
Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations. The aim of this study was to evaluate the effect of Dyrk1A on different alterations observed in the cerebellum of TS animals. TS mice were crossed with Dyrk1A +/- KO mice to obtain mice with a triplicate segment of Mmu16 that included Dyrk1A (TS +/+/+), mice with triplicate copies of the same genes that carried only two copies of Dyrk1A (TS +/+/-), euploid mice that expressed a normal dose of Dyrk1A (CO +/+) and CO animals with a single copy of Dyrk1A (CO +/-). Male mice were used for all experiments. The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume. However, it increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization. Furthermore, it improved the excitatory/inhibitory balance and walking pattern of TS +/+/- mice. These results support the hypothesis that Dyrk1A is involved in some of the structural and functional cerebellar phenotypes observed in the TS mouse model.
Assuntos
Cerebelo/patologia , Síndrome de Down/genética , Síndrome de Down/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Quinases DyrkRESUMO
Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aß plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aß species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aß peptide expression and neuroinflammation). Administration of anti-IL17 for 5â¯months, starting at the age of 7â¯months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aß1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.
Assuntos
Síndrome de Down/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Síndrome de Down/terapia , Feminino , Hipocampo/fisiologia , Interleucina-17/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Neurogênese , Neuroimunomodulação/fisiologia , Estresse Oxidativo , Fenótipo , Placa Amiloide/metabolismoRESUMO
Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS. In contrast, there is a lack of corresponding information regarding visual recognition memory. Therefore, we deemed it of interest to examine at both an anatomical and functional level the PRC of Ts65Dn mice. We found that the PRC of adult (1.5-3.5month-old) Ts65Dn mice exhibited diffused hypocellularity and neurons with a reduced spine density. No difference between Ts65Dn and euploid mice was detected in the abundance of glutamatergic and GABAergic terminals. We examined brain slices for long-term potentiation (LTP), a form of synaptic plasticity involved in long-term memory. Theta burst stimulation of intracortical fibers was used in order to elicit LTP in the superficial layers of the PRC. We found that in trisomic slices LTP had a similar time-course but a reduced magnitude in comparison with euploid slices. While exposure to the GABAA receptor antagonist picrotoxin had no effect on LTP magnitude, exposure to the GABAB receptor antagonist CGP55845 caused an increase in LTP magnitude that became even larger than in euploid slices. Western blot analysis showed increased levels of the G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in the PRC of Ts65Dn mice, consistent with triplication of the gene coding for GIRK2. This suggests that the reduced magnitude of LTP may be caused by GIRK2-dependent exaggerated GABAB receptor-mediated inhibition. Results provide novel evidence for anatomo-functional alterations in the PRC of Ts65Dn mice. These alterations may underlie trisomy-due impairment in visual recognition memory.
Assuntos
Síndrome de Down/patologia , Síndrome de Down/fisiopatologia , Plasticidade Neuronal/fisiologia , Córtex Perirrinal/anatomia & histologia , Córtex Perirrinal/fisiopatologia , Animais , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Modelos Animais de Doenças , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Técnicas de Cultura de Tecidos , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
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 (dual-specificity 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 Aß, 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, Aß 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.
Assuntos
Doença de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/patologia , Dosagem de Genes , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fragmentos de Peptídeos/metabolismo , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteínas tau/metabolismo , Quinases DyrkRESUMO
Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice - the most widely used mouse model of DS - to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice - a novel DS mouse model. Comparing young adult aneuploid mice (2.5-5.5months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12-13months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models.