RESUMO
Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of ß-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs.
Assuntos
Região CA1 Hipocampal/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/citologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Células Piramidais/citologia , Células Piramidais/fisiologia , Receptores de AMPA/genética , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Amyloid-ß (Aß) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer's disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aß degrade synapses and impair memory formation. We show that all Aß-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aß-mediated synaptic depression and spine loss. In addition, Aß oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3. Furthermore, although Aß-overproducing mice showed significant memory impairment, memories in GluA3-deficient congenics remained unaffected. These experiments indicate that the presence of GluA3-containing AMPARs is critical for Aß-mediated synaptic and cognitive deficits.
