RESUMO
The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.
Assuntos
Síndrome de Angelman/fisiopatologia , Síndrome de Angelman/psicologia , Moléculas de Adesão Celular Neuronais/administração & dosagem , Proteínas da Matriz Extracelular/administração & dosagem , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Proteínas do Tecido Nervoso/administração & dosagem , Serina Endopeptidases/administração & dosagem , Síndrome de Angelman/tratamento farmacológico , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Córtex Cerebral/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Feminino , Células HEK293 , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Humanos , Injeções Intraventriculares , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
Hippocampal neurogenesis is the lifelong production of new neurons in the central nervous system (CNS), and affects many physiological and pathophysiological conditions, including neurobehavioral disorders. The early postnatal stage is the most prominent neurogenesis period; however, the functional role of neurogenesis in this developing stage has not been well characterized. To understand the role of hippocampal neurogenesis in the postnatal developing period, we analyzed secretin, a neuropeptide, which is expressed significantly higher in the development stage. Secretin is a pleiotropic neuropeptide hormone that belongs to the secretin/VIP/glucagon peptide family. Although secretin was originally isolated in the gastrointestinal system, it has been found that secretin itself acts as a neuropeptide in the CNS. Here, we report a new function of secretin as a survival factor for neural progenitor cells in the hippocampus. We found that secretin-deficient mice exhibit decreased numbers of BrdU-labeled new neurons and dramatically increased apoptosis of doublecortin-positive neural progenitor cells in the subgranular zone of the dentate gyrus (DG) during the early postnatal period. Furthermore, we found that reduced survival of neural progenitor cells leads to decreased volume of DG, reduced long-term potentiation and impaired spatial learning ability in adults. Our studies demonstrate that secretin has important implications for neurogenesis in postnatal development, and affects neurobehavioral function in the adult mouse.
Assuntos
Neurônios/citologia , Neurônios/metabolismo , Secretina/deficiência , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Apoptose , Sobrevivência Celular , Giro Denteado/citologia , Giro Denteado/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Secretina/genéticaRESUMO
The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1â»/â», CX3CR1âº/â», and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1ß receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1ß.
Assuntos
Transtornos Cognitivos/patologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/genética , Receptores de Interleucina-8A/deficiência , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biofísica , Bromodesoxiuridina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Cerebelo/metabolismo , Transtornos Cognitivos/genética , Condicionamento Psicológico/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Comportamento Exploratório/fisiologia , Medo/fisiologia , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Atividade Motora/genética , Neurogênese/genética , Técnicas de Patch-Clamp , Teste de Desempenho do Rota-RodRESUMO
Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.
Assuntos
Encéfalo/citologia , Moléculas de Adesão Celular Neuronais/farmacologia , Cognição/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Proteínas da Matriz Extracelular/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/ultraestrutura , Serina Endopeptidases/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Proteína de Ligação a CREB/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Células HEK293/citologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Proteína Reelina , Coloração pela Prata/métodosRESUMO
Excessive glutamate (Glu) stimulation of the NMDA-R is a widely recognized trigger for Ca(2+)-mediated excitotoxicity. Primary neurons typically show a large increase in vulnerability to excitotoxicity with increasing days in vitro (DIV). This enhanced vulnerability has been associated with increased expression of the NR2B subunit or increased NMDA-R current, but the detailed age-courses of these variables in primary hippocampal neurons have not been compared in the same study. Further, it is not clear whether the NMDA-R is the only source of excess Ca(2+). Here, we used primary hippocampal neurons to examine the age dependence of the increase in excitotoxic vulnerability with changes in NMDA-R current, and subunit expression. We also tested whether L-type voltage-gated Ca(2+) channels (L-VGCCs) contribute to the enhanced vulnerability. The EC(50) for Glu toxicity decreased by approximately 10-fold between 8-9 and 14-15 DIV, changing little thereafter. Parallel experiments found that during the same period both amplitude and duration of NMDA-R current increased dramatically; this was associated with an increase in protein expression of the NR1 and NR2A subunits, but not of the NR2B subunit. Compared to MK-801, ifenprodil, a selective NR2B antagonist, was less effective in protecting older than younger neurons from Glu insult. Conversely, nimodipine, an L-VGCC antagonist, protected older but not younger neurons. Our results indicate that enhanced excitotoxic vulnerability with age in culture was associated with a substantial increase in NMDA-R current, concomitant increases in NR2A and NR1 but not NR2B subunit expression, and with apparent recruitment of L-VGCCs into the excitotoxic process.
Assuntos
Envelhecimento/fisiologia , Hipocampo/citologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Maleato de Dizocilpina/farmacologia , Embrião de Mamíferos , Feminino , Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/toxicidade , L-Lactato Desidrogenase/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Técnicas de Patch-Clamp/métodos , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Aging is accompanied by increased neuroinflammation, synaptic dysfunction, and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months), and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, glial fibrillary acidic protein, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Cognição/efeitos dos fármacos , Cognição/fisiologia , Envelhecimento Cognitivo/fisiologia , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Animais , Astrócitos/patologia , Biomarcadores/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/fisiopatologia , Potenciação de Longa Duração , Masculino , Camundongos , Terapia de Alvo Molecular , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologiaRESUMO
The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transtornos Neurológicos da Marcha/metabolismo , Deficiências da Aprendizagem/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal , Esquizofrenia/metabolismo , Serina Endopeptidases/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Cruzamentos Genéticos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Proteínas da Matriz Extracelular/genética , Feminino , Transtornos Neurológicos da Marcha/etiologia , Glutamato Descarboxilase/metabolismo , Heterozigoto , Hipocampo/metabolismo , Aprendizagem , Deficiências da Aprendizagem/etiologia , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Proteínas do Tecido Nervoso/genética , Inibição Neural , Neurônios/metabolismo , Proteína Reelina , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Filtro Sensorial , Serina Endopeptidases/genética , Transmissão SinápticaRESUMO
Low-density-lipoprotein receptors (LDLRs) are an evolutionarily ancient surface protein family with the ability to activate a diversity of extracellular signals across the cellular membrane in the adult central nervous system (CNS). Their intimate roles in modulating synaptic plasticity and their necessity in hippocampal-dependent learning and memory have only recently come to light. Two known LDLR ligands, specifically apolipoprotein E (apoE) and reelin, have been the most widely investigated in this regard. Most of our understanding of synaptic plasticity comes from investigation of both pre- and postsynaptic alterations. Therefore, it is interesting to note that neurons and glia that do not contribute to the synaptic junction in question can secrete signaling molecules that affect synaptic plasticity. Notably, reelin and apoE have been shown to modulate hippocampal long-term potentiation in general, and affect NMDA receptor and AMPA receptor regulation specifically. Furthermore, these receptors and signaling molecules have significant roles in neuronal degenerative diseases such as Alzheimer's disease. The recent production of recombinant proteins, knockout and transgenic mice for receptors and ligands and the development of human ApoE targeted replacement mice have significantly expanded our understanding of the roles LDLRs and their ligands have in certain disease states and the accompanying initiation of specific signaling pathways. This review describes the role LDLRs, apoE and reelin have in the regulation of hippocampal synaptic plasticity.