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1.
J Neurosci ; 30(34): 11414-25, 2010 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-20739563

RESUMO

Overproduction of beta-amyloid (Abeta) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on Abeta-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of Abeta in EC slices. Synaptic depression and LTD impairment induced by Abeta were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1beta (interleukin-1beta) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in Abeta-induced EC synaptic dysfunction.


Assuntos
Peptídeos beta-Amiloides/fisiologia , Córtex Entorrinal/fisiopatologia , Produtos Finais de Glicação Avançada/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Microglia/metabolismo , Receptores Imunológicos/fisiologia , Transdução de Sinais/fisiologia , Animais , Córtex Entorrinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/fisiologia , Inibição Neural/fisiologia , Receptor para Produtos Finais de Glicação Avançada
2.
J Neurosci ; 29(25): 8075-86, 2009 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-19553447

RESUMO

Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Memória/efeitos dos fármacos , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Condicionamento Clássico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Injeções Intraperitoneais , Camundongos , Camundongos Transgênicos , Mutação , Testes Neuropsicológicos , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/farmacocinética , Fosforilação/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Reação em Cadeia da Polimerase , Desempenho Psicomotor , Purinas/administração & dosagem , Purinas/farmacocinética , Purinas/farmacologia , Citrato de Sildenafila , Comportamento Espacial/efeitos dos fármacos , Sulfonas/administração & dosagem , Sulfonas/farmacocinética , Fatores de Tempo , Resultado do Tratamento
3.
J Neurosci ; 28(53): 14537-45, 2008 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-19118188

RESUMO

Amyloid-beta (Abeta) peptides are produced in high amounts during Alzheimer's disease, causing synaptic and memory dysfunction. However, they are also released in lower amounts in normal brains throughout life during synaptic activity. Here we show that low picomolar concentrations of a preparation containing both Abeta(42) monomers and oligomers cause a marked increase of hippocampal long-term potentiation, whereas high nanomolar concentrations lead to the well established reduction of potentiation. Picomolar levels of Abeta(42) also produce a pronounced enhancement of both reference and contextual fear memory. The mechanism of action of picomolar Abeta(42) on both synaptic plasticity and memory involves alpha7-containing nicotinic acetylcholine receptors. These findings strongly support a model for Abeta effects in which low concentrations play a novel positive, modulatory role on neurotransmission and memory, whereas high concentrations play the well known detrimental effect culminating in dementia.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sinapses/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/farmacologia , Análise de Variância , Animais , Bungarotoxinas/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica/métodos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Hipocampo/citologia , Humanos , Técnicas In Vitro , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/genética , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Receptores Nicotínicos/deficiência , Receptor Nicotínico de Acetilcolina alfa7
4.
Drug News Perspect ; 20(6): 365-70, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17925890

RESUMO

Impairment of the ubiquitin-proteasome system (UPS) results in the failure to remove and degrade misfolded proteins and consequently causes the accumulation of misfolded proteins in the cell. The aberrant interactions between misfolded proteins and normal intracellular proteins are thought to underlie the pathogenesis in many neurodegenerative diseases. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an important component of the UPS. Its major function is related to mono-ubiquitin recycling and thereby, sustaining protein degradation. Mutations of the UCH-L1 gene and alterations of its proteins' activity have been found to associate with several neurodegenerative disorders. In this review, we will discuss a link between UCH-L1 and Parkinson's, Huntington's and Alzheimer's diseases. We will also present a potential strategy for the treatment of Alzheimer's disease by boosting endogenous UCH-L1 activity.


Assuntos
Doença de Alzheimer/genética , Doença de Huntington/genética , Doença de Parkinson/genética , Ubiquitina Tiolesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Sistemas de Liberação de Medicamentos , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/fisiopatologia , Mutação , Doença de Parkinson/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina Tiolesterase/genética
5.
Proc Natl Acad Sci U S A ; 104(30): 12554-9, 2007 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-17640897

RESUMO

Modafinil (Provigil, Modiodal), an antinarcoleptic and mood-enhancing drug, is shown here to sharpen thalamocortical activity and to increase electrical coupling between cortical interneurons and between nerve cells in the inferior olivary nucleus. After irreversible pharmacological block of connexin permeability (i.e., by using either 18beta-glycyrrhetinic derivatives or mefloquine), modafinil restored electrotonic coupling within 30 min. It was further established that this restoration is implemented through a Ca(2+)/calmodulin protein kinase II-dependent step.


Assuntos
Compostos Benzidrílicos/farmacologia , Encéfalo/efeitos dos fármacos , Elétrons , Neurônios/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Eletrofisiologia , Camundongos , Modafinila , Neurônios/metabolismo , Ratos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
Trends Neurosci ; 28(6): 325-33, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15927689

RESUMO

Brain function is fundamentally related in the most general sense to the richness of thalamocortical interconnectivity, and in particular to the rhythmic oscillatory properties of thalamocortical loops. Such rhythmicity is involved in the genesis of cognition, in the sleep-wake cycle, and in several neurological and psychiatric disorders. The role of GABA-mediated transmission in regulating these functional states is addressed here. At the cortical level, inhibition determines the spread of cortical activation by sculpting the precise activity patterns that underlie the details of cognition and motor control. At the thalamic level, GABA-mediated inhibition modulates and resets distribution of the ongoing thalamocortical rhythmic oscillations that bind multisensory inputs into a single cognitive experience and regulate arousal levels.


Assuntos
Vias Neurais/fisiologia , Periodicidade , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Mapeamento Encefálico , Cognição/fisiologia , Sincronização Cortical/métodos , Diagnóstico por Imagem/métodos , Estimulação Elétrica/métodos , Humanos , Interneurônios/fisiologia , Magnetoencefalografia/métodos , Inibição Neural/fisiologia , Redes Neurais de Computação
7.
J Neurophysiol ; 94(4): 2447-56, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15928056

RESUMO

Inferior olivary (IO) neurons are electrically coupled through gap junctions and generate synchronous subthreshold oscillations of their membrane potential at a frequency of 1-10 Hz. Whereas the ionic mechanisms of these oscillatory responses are well understood, their origin and ensemble properties remain controversial. Here, the role of gap junctions in generating and synchronizing IO oscillations was examined by combining intracellular recordings with high-speed voltage-sensitive dye imaging in rat brain stem slices. Single cell responses and ensemble synchronized responses of IO neurons were compared in control conditions and in the presence of 18beta-glycyrrhetinic acid (18beta-GA), a pharmacological gap junction blocker. Under our experimental conditions, 18beta-GA had no adverse effects on intrinsic electroresponsive properties of IO neurons, other than the block of gap junction-dependent dye coupling and the resulting change in cells' passive properties. Application of 18beta-GA did not abolish single cell oscillations. Pharmacologically uncoupled IO neurons continued to oscillate with a frequency and amplitude that were similar to those recorded in control conditions. However, these oscillations were no longer synchronized across a population of IO neurons. Our optical recordings did not detect any clusters of synchronous oscillatory activity in the presence of the blocker. These results indicate that gap junctions are not necessary for generating subthreshold oscillations, rather, they are required for clustering of coherent oscillatory activity in the IO. The findings support the view that oscillatory properties of single IO neurons endow the system with important reset dynamics, while gap junctions are mainly required for synchronized neuronal ensemble activity.


Assuntos
Junções Comunicantes/fisiologia , Neurônios/fisiologia , Núcleo Olivar/citologia , Periodicidade , Transmissão Sináptica/fisiologia , Animais , Animais Recém-Nascidos , Biotina/análogos & derivados , Biotina/metabolismo , Contagem de Células/métodos , Interações Medicamentosas , Antagonistas GABAérgicos/farmacologia , Junções Comunicantes/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Estimulação Física/métodos , Picrotoxina/farmacologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Fatores de Tempo
8.
J Neurosci ; 22(7): 2804-15, 2002 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-11923445

RESUMO

Spatiotemporal profiles of ensemble subthreshold neuronal oscillation were studied in brainstem slices using high-speed voltage-sensitive dye imaging. After local electrical stimuli, the overall voltage profile demonstrated coherent oscillatory waves that spread over the inferior olive (IO). These oscillations were also observed in concurrently obtained intracellular recordings from IO neurons. Over the first few seconds after the stimuli, the optically recorded oscillations clustered into coherent groups comprising hundreds of neurons. Statistical analysis of the spatial profiles of these clusters revealed size fluctuation around stable core regions that were surrounded by a rim the diameter of which varied in time during the oscillation period. The neuronal ensemble oscillations were calcium derived and had an average frequency range of 1-7 Hz. This rhythmic response demonstrated a different spatiotemporal distribution in the presence of picrotoxin, which induced the merging of neuronal clusters into larger areas of coherent activity. The possibility that such clustering is a consequence of intrinsic oscillations in ensembles of coupled neurons was tested using mathematical modeling.


Assuntos
Relógios Biológicos/fisiologia , Rede Nervosa/fisiologia , Redes Neurais de Computação , Neurônios/fisiologia , Núcleo Olivar/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Relógios Biológicos/efeitos dos fármacos , Simulação por Computador , Estimulação Elétrica , Corantes Fluorescentes , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Potenciais da Membrana/fisiologia , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Núcleo Olivar/citologia , Núcleo Olivar/efeitos dos fármacos , Óptica e Fotônica , Periodicidade , Picrotoxina/farmacologia , Compostos de Piridínio , Ratos , Ratos Sprague-Dawley , Processamento de Sinais Assistido por Computador
9.
Proc Natl Acad Sci U S A ; 99(1): 449-54, 2002 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-11773628

RESUMO

Voltage-sensitive dye imaging of mouse thalamocortical slices demonstrated that electrical stimulation of the centrolateral intralaminar thalamic nucleus (CL) resulted in the specific activation of thalamic reticular nucleus, striatum/putamen, and cortical layers 5, 6, and 1. By contrast, ventrobasal (VB) thalamic stimulation, while activating the reticular and basal ganglia nuclei, also activated directly layers 4 and deep 5 of the cortex. Conjoined stimulation of the VB and CL nuclei resulted in supralinear summation of the two inputs at cortical output layer 5, demonstrating coincidence detection along the apical dendrites. This supralinear summation was also noticed at gamma band stimulus frequency ( approximately 40 Hz). Direct stimulation of cortical layer 1, after a radial section of the cortex that spared only that layer, was shown to sum supralinearly with the cortical activation triggered by VB stimulation, providing a second demonstration for coincidence detection. Coincidence detection by coactivation of the specific (VB) and nonspecific (CL) thalamic nuclei has been proposed as the basis for the temporal conjunction that supports cognitive binding in the brain.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/patologia , Córtex Cerebral/patologia , Núcleos Talâmicos/fisiologia , Tálamo/patologia , Animais , Núcleo Celular/metabolismo , Córtex Cerebral/anatomia & histologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Corpos de Nissl/metabolismo , Ligação Proteica , Tálamo/anatomia & histologia , Fatores de Tempo
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