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1.
Acta Neuropathol Commun ; 7(1): 27, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808398

RESUMO

The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence, were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of FMRpolyG, and deficits in motor function.

2.
J Comp Psychol ; 131(3): 189-206, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28333487

RESUMO

We propose and validate a clear strategy to efficiently and comprehensively characterize neurobehavioral deficits in the Ts65Dn mouse model of Down syndrome. This novel approach uses neurocognitive theory to design and select behavioral tasks that test specific hypotheses concerning the results of Down syndrome. In this article, we model the Arizona Cognitive Task Battery, used to study human populations with Down syndrome, in Ts65Dn mice. We observed specific deficits for spatial memory, impaired long-term memory for visual objects, acquisition and reversal of motor responses, reduced motor dexterity, and impaired adaptive function as measured by nesting and anxiety tasks. The Ts65Dn mice showed intact temporal ordering, novelty detection, and visual object recognition with short delays. These results phenocopy the performance of participants with Down syndrome on the Arizona Cognitive Task Battery. This approach extends the utility of mouse models of Down syndrome by integrating the expertise of clinical neurology and cognitive neuroscience into the mouse behavioral laboratory. Further, by directly emphasizing the reciprocal translation of research between human disease states and the associated mouse models, we demonstrate that it is possible for both groups to mutually inform each other's research to more efficiently generate hypotheses and elucidate treatment strategies. (PsycINFO Database Record


Assuntos
Cognição , Síndrome de Down/diagnóstico , Testes Neuropsicológicos , Percepção Visual , Animais , Modelos Animais de Doenças , Camundongos , Análise e Desempenho de Tarefas
3.
J Psychiatry Neurosci ; 41(3): 203-13, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26599134

RESUMO

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population. METHODS: We measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety. RESULTS: We included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group. LIMITATIONS: Shape alterations are not specific to hippocampal subfields. CONCLUSION: Alterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection.


Assuntos
Ansiedade/diagnóstico por imagem , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/psicologia , Hipocampo/diagnóstico por imagem , Adolescente , Criança , Feminino , Hipocampo/crescimento & desenvolvimento , Humanos , Processamento de Imagem Assistida por Computador , Inteligência , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão , Prognóstico , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Caracteres Sexuais
4.
PLoS One ; 9(2): e89456, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586791

RESUMO

This report outlines a neuroimaging pipeline that allows a robust, high-throughput, semi-automated, template-based protocol for segmenting the hippocampus in rhesus macaque (Macaca mulatta) monkeys ranging from 1 week to 260 weeks of age. The semiautomated component of this approach minimizes user effort while concurrently maximizing the benefit of human expertise by requiring as few as 10 landmarks to be placed on images of each hippocampus to guide registration. Any systematic errors in the normalization process are corrected using a machine-learning algorithm that has been trained by comparing manual and automated segmentations to identify systematic errors. These methods result in high spatial overlap and reliability when compared with the results of manual tracing protocols. They also dramatically reduce the time to acquire data, an important consideration in large-scale neuroradiological studies involving hundreds of MRI scans. Importantly, other than the initial generation of the unbiased template, this approach requires only modest neuroanatomical training. It has been validated for high-throughput studies of rhesus macaque hippocampal anatomy across a broad age range.


Assuntos
Hipocampo/fisiologia , Interpretação de Imagem Assistida por Computador/métodos , Macaca mulatta/fisiologia , Neuroimagem/métodos , Reconhecimento Automatizado de Padrão/métodos , Algoritmos , Animais , Inteligência Artificial , Feminino , Imagem Tridimensional/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Reprodutibilidade dos Testes
5.
Hippocampus ; 24(7): 794-807, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24648155

RESUMO

Nonhuman primates are widely used models to investigate the neural substrates of human behavior, including the development of higher cognitive and affective function. Due to their neuroanatomical and behavioral homologies with humans, the rhesus macaque monkey (Macaca mulatta) provides an excellent animal model in which to characterize the maturation of brain structures from birth through adulthood and into senescence. To evaluate hippocampal development in rhesus macaques, structural magnetic resonance imaging scans were obtained longitudinally at 9 time points between 1 week and 260 weeks (5 years) of age on 24 rhesus macaque monkeys (12 males, 12 females). In our sample, the hippocampus reaches 50% of its adult volume by 13 weeks of age and reaches an adult volume by 52 weeks in both males and females. The hippocampus appears to be slightly larger at 3 years than at 5 years of age. Male rhesus macaques have larger hippocampi than females from 8 weeks onward by approximately 5%. Interestingly, there was increased variability in hemispheric asymmetry for hippocampus volumes at younger ages than at later ages. These data provide a comprehensive evaluation of the longitudinal development of male and female rhesus macaque hippocampus across development from 1 week to 5 years of age.


Assuntos
Hipocampo/crescimento & desenvolvimento , Macaca mulatta/crescimento & desenvolvimento , Imagem por Ressonância Magnética , Neuroimagem , Animais , Feminino , Masculino , Tamanho do Órgão , Caracteres Sexuais
6.
Neurobiol Learn Mem ; 109: 160-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24462720

RESUMO

Environmental enrichment results in increased levels of Fmrp in brain and increased dendritic complexity. The present experiment evaluated activity-dependent increases in Fmrp levels in the motor cortex in response to training on a skilled forelimb reaching task in the CGG KI mouse model of the fragile X premutation. Fmrp, Arc, and c-Fos protein levels were quantified by Western blot in the contralateral motor cortex of mice following training to reach for sucrose pellets with a non-preferred paw and compared to levels in the ipsilateral motor cortex. After training, all mice showed increases in Fmrp, Arc, and c-Fos protein levels in the contralateral compared to the ipsilateral hemisphere; however, the increase in CGG KI mice was less than wildtype mice. Increases in Fmrp and Arc proteins scaled with learning, whereas this relationship was not observed with the c-Fos levels. These data suggest the possibility that reduced levels of activity-dependent proteins associated with synaptic plasticity such as Fmrp and Arc may contribute to the neurocognitive phenotype reported in the CGG KI mice and the fragile X premutation.


Assuntos
Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Atividade Motora/fisiologia , Córtex Motor/metabolismo , Animais , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Técnicas de Introdução de Genes , Masculino , Camundongos , Mutação
7.
Transl Neurodegener ; 2(1): 10, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23692864

RESUMO

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55-200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45-54 CGG repeats) as well as in a subject with a full mutation with mosaicism.Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.

8.
Hippocampus ; 23(5): 380-91, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23436324

RESUMO

It has been suggested that the role of the hippocampus for episodic memory is to selectively bind together item and contextual information. One such model, the Binding of Items and Context (BIC) model, proposed that the perirhinal cortex provides item and the postrhinal/parahippocampal cortex provides context to the hippocampus via the medial (MEC) and lateral entorhinal cortices (LEC) to be bound into an episodic representation. This model proposes that item and context information are stored and processed independently and in parallel before hippocampal processing. To evaluate this model, the present experiment evaluated the role of the MEC and LEC for item and contextual novelty detection. The present results suggest that excitotoxic lesions to the LEC primarily disrupt item novelty detection, whereas lesions to the MEC primarily disrupt contextual novelty detection. These data provide a functional double dissociation between the MEC and LEC across item and contextual processing. Despite this dissociation, the present results suggest that item and contextual information are not represented independently before hippocampal processing. These data support the basic assumptions of the BIC model, but suggest that item and context information may interact in the entorhinal cortex.


Assuntos
Córtex Entorrinal/fisiologia , Memória Episódica , Modelos Psicológicos , Detecção de Sinal Psicológico/fisiologia , Animais , Córtex Entorrinal/anatomia & histologia , Córtex Entorrinal/lesões , Agonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/fisiologia , Hipocampo/lesões , Hipocampo/fisiologia , Ácido Ibotênico/toxicidade , Masculino , Vias Neurais/fisiologia , Estimulação Luminosa , Ratos , Ratos Long-Evans
9.
J Neurotrauma ; 30(4): 292-300, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23140483

RESUMO

Impairments in learning and memory occur in as many as 50% of patients following traumatic brain injury (TBI). Similar impairments occur in rodent models of TBI, and the development of new memory testing procedures provides an opportunity to examine how TBI affects memory processing in specific neural memory systems. Specifically, metric, topological, and temporal ordering tasks are object-based tests for memory of spatial orientation and temporal sequencing working memory developed for use in rodents. Previous studies demonstrated that specific lesions of the dentate gyrus/CA3 of the hippocampus and the parietal cortex resulted in deficits in the metric and topological spatial orientation tasks, respectively. Lesions of the CA1 impaired a rat's ability to recall the temporal order of odors. The purpose of the following study was to determine whether moderate lateral fluid percussion TBI would generate deficits in these working memory tasks, and whether observed deficits were associated with cell loss in the CA2/3 and/or CA1 of the hippocampus. Two weeks following a moderate lateral fluid percussion TBI, adult rats demonstrated significant deficits in both the metric and temporal ordering tasks (p<0.05) but not in the topological task. Stereological analysis identified a significant reduction in neurons in the CA2/3 (p<0.05) but not the CA1 of the hippocampus. These data demonstrate the utility of three object-based tasks to expand our understanding of how different neural memory systems are affected by TBI.


Assuntos
Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Hipocampo/patologia , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Animais , Modelos Animais de Doenças , Ratos , Ratos Sprague-Dawley
10.
Neurosci Biobehav Rev ; 37(1): 36-58, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23043857

RESUMO

Pattern separation and pattern completion processes are central to how the brain processes information in an efficient manner. Research into these processes is escalating and deficient pattern separation is being implicated in a wide array of genetic disorders as well as in neurocognitive aging. Despite the quantity of research, there remains a controversy as to precisely which behavioral paradigms should be used to best tap into pattern separation and pattern completion processes, as well as to what constitute legitimate outcome measures reflecting impairments in pattern separation and pattern completion. This review will discuss a theory based on multiple memory systems that provides a framework upon which behavioral tasks can be designed and their results interpreted. Furthermore, this review will discuss the nature of pattern separation and pattern completion and extend these processes outside the hippocampus and across all domains of information processing. After these discussions, an optimal strategy for designing behavioral paradigms to evaluate pattern separation and pattern completion processes will be provided.


Assuntos
Simulação por Computador , Memória/fisiologia , Modelos Psicológicos , Reconhecimento Fisiológico de Modelo/fisiologia , Percepção/fisiologia , Animais , Hipocampo/fisiologia , Humanos
11.
F1000Res ; 2: 287, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24627796

RESUMO

It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on the FMR1 gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to the Fmr1 knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X-Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

12.
Brain Res ; 1472: 124-37, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22796595

RESUMO

The fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansions in the fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and in astroglia. Intranuclear inclusions have also been reported in the neurons of male CGG KI mice carrying an expanded CGG trinucleotide repeat and used to model FXTAS, but no study has been carried out quantifying inclusions in female CGG KI mice heterozygous for the fragile X premutation. We used histologic and immunocytochemical methods to determine the pathological features of intranuclear inclusions in astroglia and neurons. In female CGG KI mice, ubiquitin-positive intranuclear inclusions were found in neurons and astroglia throughout the brain in cortical and subcortical regions. These inclusions increased in number and became larger with advanced age and increasing CGG repeat length, supporting hypotheses that these pathologic features are progressive across the lifespan. The number of inclusions in neurons was reduced by ∼25% in female CGG KI mice compared to male CGG KI mice, but not so low as the 50% predicted. These data emphasize the need to evaluate the neurocognitive and pathological features in female carriers of the fragile X premutation with and without FXTAS symptomatology is warranted, as this population shows similar neuropathological features present in male FXTAS patients.


Assuntos
Astrócitos/patologia , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/patologia , Corpos de Inclusão Intranuclear/patologia , Neurônios/patologia , Idoso , Animais , Modelos Animais de Doenças , Feminino , Imunofluorescência , Síndrome do Cromossomo X Frágil/genética , Heterozigoto , Humanos , Imuno-Histoquímica , Camundongos , Microscopia Confocal , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Repetições de Trinucleotídeos
13.
Hippocampus ; 22(12): 2260-75, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22707411

RESUMO

The fragile X premutation is a CGG repeat expansion on the FMR1 gene between 55 and 200 repeats in length. It has been proposed that impaired spatiotemporal function underlies cognitive deficits in genetic disorders, including the fragile X premutation. This study characterized the role of the premutation for cognitive function by demonstrating CGG KI mice with 70-198 CGG repeats show deficits across tasks requiring spatial and temporal pattern separation. To elucidate mechanisms whereby CGG repeats affect spatiotemporal processing, hippocampal slices were evaluated for LTP, LTD, and mGluR1/5 LTD. Increasing CGG repeat length modulated the induction of LTP, LTD, and mGluR1/5 LTD, as well as behavioral tasks emphasizing spatiotemporal processing. Despite the deficits in the induction of all forms of plasticity, there were no differences in expression of plasticity once evoked. These data provide evidence for a neurocognitive endophenotype in the CGG KI mouse model of the premutation in which CGG repeat length negatively modulates plasticity and spatiotemporal attention.


Assuntos
Comportamento Animal/fisiologia , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Plasticidade Neuronal/fisiologia , Repetições de Trinucleotídeos/genética , Animais , Análise por Conglomerados , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/fisiopatologia , Genótipo , Humanos , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Máquina de Vetores de Suporte
14.
Behav Neurosci ; 126(3): 371-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22642882

RESUMO

In order to overcome difficulties in evaluating cognitive function in mouse models of genetic disorders, it is critical to take into account the background strain of the mouse and reported phenotypes in the clinical population being studied. Recent studies have evaluated cognitive function across a number of background strains and found that spatial memory assayed by the water maze and contextual fear conditioning often does not provide optimal results. The logical extension to these results is to emphasize not only spatial, but all attributes or domains of memory function in behavioral phenotyping experiments. A careful evaluation of spatial, temporal, sensory/perceptual, affective, response, executive, proto-linguistic, and social behaviors designed to specifically evaluate the cognitive function each mouse model can be performed in a rapid, relatively high throughput manner. Such results would not only provide a more comprehensive snapshot of brain function in mouse disease models than the more common approach that approaches nonspecific spatial memory tasks to evaluate cognition, but also would better model the disorders being studied.


Assuntos
Comportamento Animal/fisiologia , Modelos Animais de Doenças , Endofenótipos , Transtornos da Memória/genética , Memória/fisiologia , Animais , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Humanos , Transtornos da Memória/psicologia , Camundongos , Especificidade da Espécie
15.
Behav Brain Res ; 233(1): 29-34, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22561129

RESUMO

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. It has been suggested that carriers of the premutation demonstrate a spatiotemporal hypergranularity, or reduced resolution of spatial and temporal processing. A temporal ordering of spatial locations task was used to evaluate the ability of CGG KI mice to process temporal and spatial information with either high or low levels of spatial interference. The results indicate that CGG KI mice showed difficulty performing a spatial novelty detection task when there were high levels of spatial interference, but were able to perform the novelty detection task when there was low spatial interference. These data suggest that CGG KI mice show reduced spatial and temporal resolution that are modulated by the dosage of the Fmr1 gene mutation, such that when behavioral tasks require mice to overcome high levels of either spatial or temporal interference, the CGG KI mice perform increasingly poorly as the CGG repeat length increases.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/genética , Transtornos da Percepção/etiologia , Comportamento Espacial/fisiologia , Expansão das Repetições de Trinucleotídeos/genética , Animais , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Genótipo , Humanos , Locomoção/genética , Camundongos , Camundongos Transgênicos , Percepção Espacial/fisiologia
16.
Epilepsia ; 53 Suppl 1: 150-60, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22612820

RESUMO

The fragile X mental retardation 1 gene (Fmr1) is polymorphic for CGG trinucleotide repeat number in the 5'-untranslated region, with repeat lengths <45 associated with typical development and repeat lengths >200 resulting in hypermethylation and transcriptional silencing of the gene and mental retardation in the fragile X Syndrome (FXS). Individuals with CGG repeat expansions between 55 and 200 are carriers of the fragile X premutation (PM). PM carriers show a phenotype that can include anxiety, depression, social phobia, and memory deficits. They are also at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by tremor, ataxia, cognitive impairment, and neuropathologic features including intranuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and white matter disease. However, very little is known about dendritic morphology in PM or in FXTAS. Therefore, we carried out a Golgi study of dendritic complexity and dendritic spine morphology in layer II/III pyramidal neurons in primary visual cortex in a knock-in (KI) mouse model of the PM. These CGG KI mice carry an expanded CGG trinucleotide repeat on Fmr1, and model many features of the PM and FXTAS. Compared to wild-type (WT) mice, CGG KI mice showed fewer dendritic branches proximal to the soma, reduced total dendritic length, and a higher frequency of longer dendritic spines. The distribution of morphologic spine types (e.g., stubby, mushroom, filopodial) did not differ between WT and KI mice. These findings demonstrate that synaptic circuitry is abnormal in visual cortex of mice used to model the PM, and suggest that such changes may underlie neurologic features found in individuals carrying the PM as well as in individuals with FXTAS.


Assuntos
Dendritos/patologia , Espinhas Dendríticas/patologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Repetições de Trinucleotídeos/genética , Córtex Visual/patologia , Regiões 5' não Traduzidas/genética , Animais , Animais Geneticamente Modificados , Ataxia/genética , Ataxia/patologia , Western Blotting , Interpretação Estatística de Dados , Proteína do X Frágil de Retardo Mental/genética , Genótipo , Complexo de Golgi/patologia , Processamento de Imagem Assistida por Computador , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Mutação/fisiologia , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Sinapses/patologia , Sinapses/ultraestrutura
17.
Prog Neurobiol ; 96(2): 220-41, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22266125

RESUMO

There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species.


Assuntos
Comportamento/fisiologia , Cognição/fisiologia , Modelos Animais de Doenças , Endofenótipos , Animais , Cromossomos Humanos Par 22 , Deleção de Genes , Humanos , Camundongos
18.
Results Probl Cell Differ ; 54: 255-69, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22009357

RESUMO

The use of mutant mouse models of neurodevelopmental and neurodegenerative disease is essential in order to understand the pathogenesis of many genetic diseases such as fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). The choice of which animal model is most suitable to mimic a particular disease depends on a range of factors, including anatomical, physiological, and pathological similarities; presence of orthologs of genes of interest; and conservation of basic cell biological and metabolic processes. In this chapter, we will discuss two mouse models of the fragile X premutation which have been generated to study the pathogenesis of FXTAS and the effects of potential therapeutic interventions. Behavioral, molecular, neuropathological, and endocrine features of the mouse models and their relation to human FXTAS are discussed.


Assuntos
Ataxia/etiologia , Ataxia/fisiopatologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/complicações , Tremor/etiologia , Tremor/fisiopatologia , Animais , Comportamento Animal/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Mutação
19.
Neurobiol Learn Mem ; 97(2): 229-34, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22202169

RESUMO

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. Previous studies have demonstrated that CGG KI mice have spatiotemporal information processing deficits and impaired visuomotor function that worsen with increasing CGG repeat length. Since skilled forelimb reaching requires integration of information from the visual and motor systems, skilled reaching performance could identify potential visuomotor dysfunction in CGG KI mice. To characterize motor deficits associated with the fragile X premutation, 6 month old female CGG KI mice heterozygous for trinucleotide repeats ranging from 70-200 CGG in length were tested for their ability to learn a skilled forelimb reaching task. The results demonstrate that female CGG KI mice show deficits for learning a skilled forelimb reaching task compared to wildtype littermates, and that these deficits worsen with increasing CGG repeat lengths.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Expansão das Repetições de Trinucleotídeos , Animais , Comportamento Animal/fisiologia , Feminino , Membro Anterior/fisiopatologia , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos
20.
Acta Neuropathol ; 122(4): 467-79, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21785977

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic organ systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.


Assuntos
Ataxia/patologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Triagem de Portadores Genéticos , Tremor/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Ataxia/genética , Modelos Animais de Doenças , Feminino , Proteína do X Frágil de Retardo Mental/genética , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Mutantes , Especificidade de Órgãos/genética , Tremor/genética
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