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1.
Cereb Cortex ; 30(3): 1688-1707, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-31667489

RESUMO

Reelin is an extracellular matrix protein, known for its dual role in neuronal migration during brain development and in synaptic plasticity at adult stages. During the perinatal phase, Reelin expression switches from Cajal-Retzius (CR) cells, its main source before birth, to inhibitory interneurons (IN), the main source of Reelin in the adult forebrain. IN-derived Reelin has been associated with schizophrenia and temporal lobe epilepsy; however, the functional role of Reelin from INs is presently unclear. In this study, we used conditional knockout mice, which lack Reelin expression specifically in inhibitory INs, leading to a substantial reduction in total Reelin expression in the neocortex and dentate gyrus. Our results show that IN-specific Reelin knockout mice exhibit normal neuronal layering and normal behavior, including spatial reference memory. Although INs are the major source of Reelin within the adult stem cell niche, Reelin from INs does not contribute substantially to normal adult neurogenesis. While a closer look at the dentate gyrus revealed some unexpected alterations at the cellular level, including an increase in the number of Reelin expressing CR cells, overall our data suggest that Reelin derived from INs is less critical for cortex development and function than Reelin expressed by CR cells.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Giro Denteado/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Interneurônios/metabolismo , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Animais , Comportamento Animal/fisiologia , Movimento Celular/fisiologia , Giro Denteado/fisiopatologia , Hipocampo/metabolismo , Interneurônios/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese/fisiologia , Neurônios/metabolismo , Folhas de Planta/metabolismo , Proteína Reelina
2.
J Neurosci ; 39(41): 8149-8163, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31488612

RESUMO

Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional Arc/Arg3.1 knock-out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which Arc/Arg3.1 was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.SIGNIFICANCE STATEMENT The activity-regulated and memory-linked gene Arc/Arg3.1 has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/fisiopatologia , Psicologia do Esquizofrênico , Animais , Proteínas do Citoesqueleto/deficiência , Neurônios Dopaminérgicos , Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados , Potenciais Pós-Sinápticos Excitadores , Feminino , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/deficiência , Neurônios , Técnicas de Patch-Clamp , Reflexo de Sobressalto/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/genética , Filtro Sensorial , Comportamento Social
3.
Learn Mem ; 19(7): 268-81, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22700469

RESUMO

The synaptic Ras/Rap-GTPase-activating protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D-aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters, many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity.


Assuntos
Hipocampo/citologia , Deficiências da Aprendizagem/genética , Neurônios/fisiologia , Transmissão Sináptica/genética , Proteínas Ativadoras de ras GTPase/deficiência , Análise de Variância , Animais , Aprendizagem da Esquiva/fisiologia , Proteínas do Domínio Duplacortina , Regulação da Expressão Gênica/genética , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Hipocampo/metabolismo , Integrases/genética , Integrases/metabolismo , Aprendizagem em Labirinto/fisiologia , Potenciais da Membrana/genética , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neuropeptídeos/metabolismo , Técnicas de Patch-Clamp , Tempo de Reação/genética , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Comportamento Espacial/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transdução Genética , Proteínas Ativadoras de ras GTPase/metabolismo
4.
Commun Biol ; 5(1): 589, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705737

RESUMO

Muskelin (Mkln1) is implicated in neuronal function, regulating plasma membrane receptor trafficking. However, its influence on intrinsic brain activity and corresponding behavioral processes remains unclear. Here we show that murine Mkln1 knockout causes non-habituating locomotor activity, increased exploratory drive, and decreased locomotor response to amphetamine. Muskelin deficiency impairs social novelty detection while promoting the retention of spatial reference memory and fear extinction recall. This is strongly mirrored in either weaker or stronger resting-state functional connectivity between critical circuits mediating locomotor exploration and cognition. We show that Mkln1 deletion alters dendrite branching and spine structure, coinciding with enhanced AMPAR-mediated synaptic transmission but selective impairment in synaptic potentiation maintenance. We identify muskelin at excitatory synapses and highlight its role in regulating dendritic spine actin stability. Our findings point to aberrant spine actin modulation and changes in glutamatergic synaptic function as critical mechanisms that contribute to the neurobehavioral phenotype arising from Mkln1 ablation.


Assuntos
Actinas , Extinção Psicológica , Actinas/metabolismo , Animais , Encéfalo/metabolismo , Cognição , Medo , Camundongos
5.
Eur J Neurosci ; 31(3): 529-43, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20105235

RESUMO

The brain-specific Ras/Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG(+/-)), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG(+/-) mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG(+/-) mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG(+/-) mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG(+/-) mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.


Assuntos
Comportamento Animal/fisiologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Proteínas Ativadoras de ras GTPase , Animais , Feminino , Hipocampo/citologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/metabolismo , Testes Neuropsicológicos , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo
6.
Sci Rep ; 9(1): 15940, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685876

RESUMO

Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.


Assuntos
Diferenciação Celular , Katanina/genética , Microtúbulos/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Fatores Etários , Alelos , Animais , Diferenciação Celular/genética , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Giro Denteado/embriologia , Giro Denteado/metabolismo , Marcação de Genes , Haploinsuficiência , Katanina/metabolismo , Aprendizagem , Memória , Camundongos , Camundongos Knockout , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Organogênese , Fenótipo
7.
Cell Rep ; 23(9): 2705-2717, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29847800

RESUMO

Autism spectrum disorders (ASDs) are associated with mutations affecting synaptic components, including GluN2B-NMDA receptors (NMDARs) and neurobeachin (NBEA). NBEA participates in biosynthetic pathways to regulate synapse receptor targeting, synaptic function, cognition, and social behavior. However, the role of NBEA-mediated transport in specific trafficking routes is unclear. Here, we highlight an additional function for NBEA in the local delivery and surface re-insertion of synaptic receptors in mouse neurons. NBEA dynamically interacts with Rab4-positive recycling endosomes, transiently enters spines in an activity-dependent manner, and regulates GluN2B-NMDAR recycling. Furthermore, we show that the microtubule growth inhibitor kinesin KIF21B constrains NBEA dynamics and is present in the NBEA-recycling endosome-NMDAR complex. Notably, Kif21b knockout decreases NMDAR surface expression and alters social behavior in mice, consistent with reported social deficits in Nbea mutants. The influence of NBEA-KIF21B interactions on GluN2B-NMDAR local recycling may be relevant to mechanisms underlying ASD etiology.


Assuntos
Comportamento Animal , Proteínas de Transporte/metabolismo , Endocitose , Cinesinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Comportamento Social , Animais , Células COS , Chlorocebus aethiops , Cognição , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Dineínas/metabolismo , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Ácido Glutâmico/farmacologia , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Proteínas de Membrana , Camundongos Knockout , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Nocodazol/farmacologia , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismo , Proteínas rab4 de Ligação ao GTP/metabolismo
8.
Neuron ; 99(6): 1155-1169.e9, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30174115

RESUMO

Cellular prion protein (PrPC) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrPC undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrPC and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrPC trafficking that also link intracellular and extracellular PrPC turnover. PrPC associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrPC transport and facilitates lysosomal degradation over exosomal PrPC release. Muskelin gene knockout consequently causes PrPC accumulation at the neuronal surface and on secreted exosomes. Moreover, prion disease onset is accelerated following injection of pathogenic prions into muskelin knockout mice. Our data identify an essential checkpoint in PrPC turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.


Assuntos
Membrana Celular/metabolismo , Exossomos/metabolismo , Lisossomos/metabolismo , Proteínas Priônicas/metabolismo , Animais , Progressão da Doença , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Príons/metabolismo , Transporte Proteico/fisiologia , Vesículas Transportadoras/metabolismo
9.
Cell Rep ; 15(5): 968-977, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27117409

RESUMO

The kinesin KIF21B is implicated in several human neurological disorders, including delayed cognitive development, yet it remains unclear how KIF21B dysfunction may contribute to pathology. One limitation is that relatively little is known about KIF21B-mediated physiological functions. Here, we generated Kif21b knockout mice and used cellular assays to investigate the relevance of KIF21B in neuronal and in vivo function. We show that KIF21B is a processive motor protein and identify an additional role for KIF21B in regulating microtubule dynamics. In neurons lacking KIF21B, microtubules grow more slowly and persistently, leading to tighter packing in dendrites. KIF21B-deficient neurons exhibit decreased dendritic arbor complexity and reduced spine density, which correlate with deficits in synaptic transmission. Consistent with these observations, Kif21b-null mice exhibit behavioral changes involving learning and memory deficits. Our study provides insight into the cellular function of KIF21B and the basis for cognitive decline resulting from KIF21B dysregulation.


Assuntos
Forma Celular , Cinesinas/metabolismo , Memória/fisiologia , Microtúbulos/metabolismo , Neurônios/citologia , Sinapses/metabolismo , Animais , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Marcação de Genes , Células HeLa , Humanos , Cinesinas/deficiência , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos Knockout , Microtúbulos/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Reprodutibilidade dos Testes
10.
Nat Commun ; 6: 6872, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25891999

RESUMO

Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Aprendizagem/fisiologia , Proteínas de Membrana/metabolismo , Receptores de GABA-A/metabolismo , Sinapses/fisiologia , Animais , Proteínas do Citoesqueleto/genética , Fenômenos Eletrofisiológicos , Regulação da Expressão Gênica/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Receptores de GABA-A/genética
11.
Behav Neurosci ; 123(5): 1114-28, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19824778

RESUMO

The synaptic Ras/Rap-GTPase-activating protein (SynGAP) regulates specific intracellular events following N-methyl-d-aspartate receptor (NMDAR) activation. Here, the impact of SynGAP heterozygous knockout (SG+/-) on NMDAR-dependent functions was assessed using different positive reinforcement schedules in instrumental conditioning. The knockout did not affect the temporal control of operant responding under a fixed interval (FI) schedule, but led to a putative enhancement in response vigor and/or disinhibition. When examined on differential reinforcement of low rates of response (DRL) schedules, SG+/- mice showed increased responding under DRL-4s and DRL-8s, without impairing the response efficiency (total rewards/total lever presses) because both rewarded and nonrewarded presses were elevated. Motivation was unaffected as evaluated using a progressive ratio (PR) schedule. Yet, SG+/- mice persisted in responding during extinction at the end of PR training, although an equivalent phenotype was not evident in extinction learning following FI-20s training. This extinction phenotype is therefore schedule-specific and cannot be generalized to Pavlovian conditioning. In conclusion, constitutive SynGAP reduction increases vigor in the execution of learned operant behavior without compromising its temporal control, yielding effects readily distinguishable from NMDAR blockade.


Assuntos
Condicionamento Operante/fisiologia , Motivação , Proteínas Ativadoras de ras GTPase/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Condicionamento Clássico/fisiologia , Eletrochoque , Extinção Psicológica/fisiologia , Feminino , Reação de Congelamento Cataléptica/fisiologia , Genótipo , Heterozigoto , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Esquema de Reforço , Recompensa , Fatores de Tempo , Percepção do Tempo/fisiologia , Proteínas Ativadoras de ras GTPase/genética
12.
Neurobiol Aging ; 30(5): 697-716, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-17904250

RESUMO

Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Placa Amiloide/metabolismo , Serina Endopeptidases/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Callithrix , Moléculas de Adesão Celular Neuronais/análise , Proteínas da Matriz Extracelular/análise , Feminino , Técnicas de Introdução de Genes , Hipocampo/patologia , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/análise , Neurônios/patologia , Placa Amiloide/patologia , Ratos , Ratos Wistar , Proteína Reelina , Fatores de Risco , Serina Endopeptidases/análise , Proteínas ras/genética , Proteínas tau/genética
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