Sílvia Silva

Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice.

Insulin‐like growth factor 2 (IGF2) was recently found to play a critical role in memory consolidation in rats and mice, and hippocampal or systemic administration of recombinant IGF2 enhances memory. Here, using a gene therapy‐based approach with adeno‐associated virus (AAV), we show that IGF2 overexpression in the hippocampus of aged wild‐type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF2 expression decreases in the hippocampus of patients with Alzheimers disease, and this leads us to hypothesize that increased IGF2 levels may be beneficial for treating the disease. Thus, we used the AAV system to deliver IGF2 or IGF1 into the hippocampus of the APP mouse model Tg2576 and demonstrate that IGF2 and insulin‐like growth factor 1 (IGF1) rescue behavioural deficits, promote dendritic spine formation and restore normal hippocampal excitatory synaptic transmission. The brains of Tg2576 mice that overexpress IGF2 but not IGF1 also show a significant reduction in amyloid levels. This reduction probably occurs through an interaction with the IGF2 receptor (IGF2R). Hence, IGF2 and, to a lesser extent, IGF1 may be effective treatments for Alzheimers disease.

Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.

Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimers disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.

Membrane Lipids Tune Synaptic Transmission by Direct Modulation of Presynaptic Potassium Channels

Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

Alzheimers disease (AD) is emerging as a synaptopathology driven by metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the downstream Ca2+-dependent signaling molecules that mediate aberrant metaplasticity are unknown. In this study, we show that oAβ promotes the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) via GluN2B-containing NMDARs. Importantly, we find that CaMKII inhibition rescues both the LTP impairment and the dendritic spine loss mediated by oAβ. Mechanistically resembling metaplasticity, oAβ prevents subsequent rounds of plasticity from inducing CaMKII T286 autophosphorylation, as well as the associated anchoring and accumulation of synaptic AMPA receptors (AMPARs). Finally, prolonged oAβ treatment-induced CaMKII misactivation leads to dendritic spine loss via the destabilization of surface AMPARs. Thus, our study demonstrates that oAβ engages synaptic metaplasticity via aberrant CaMKII activation.

L’émigration portugaise qualifiée dans le contexte européen

Devant le renouvellement de l’emigration portugaise en Europe, une enquete realisee en 2014 fait le point sur les representations que les migrants portent sur leur propre parcours. La distinction de differents facteurs de repulsion pour leur pays d’origine et d’attraction pour le pays de destination permet d’esquisser les nouveaux visages des migrants portugais, plus qualifies que leurs predecesseurs, tres informes sur les perspectives professionnelles de mobilite. Envisageant leur depart davantage comme une experience de vie qu’une situation d’emigration, ils contribuent a redefinir les contours transnationaux de l’Europe contemporaine.

The decision to emigrate: a study from the perspective of dispositional plurality

This paper analyses the Portuguese high-skilled emigration, focusing on the emigration decision-making process. This article aims to understand the dispositions leading to this decision, and the social processes that explain its origin, sedimentation and activation. To this end, and using the theoretical and methodological approach of Bernard Lahire, 53 sociological portraits of skilled Portuguese who emigrated to other European countries are cross-sectional analyzed. This analysis is supplemented by data from a survey previously administered. Thus, we will address how the migratory dispositions are built through the individual biographies, highlighting the heuristic potential of the individual observation scale.Este artigo analisa a emigracao portuguesa qualificada, focando-se sobre a producao da decisao de emigrar. E seu objetivo compreender as disposicoes que conduzem a essa decisao, bem como os processos sociais que explicam a sua genese, sedimentacao e ativacao. Para isso, e recorrendo a proposta teorica e metodologica de Bernard Lahire, procede-se a analise transversal de 53 retratos sociologicos de portugueses qualificados que emigraram para outros paises europeus, complementada pelos dados de um inquerito administrado previamente. Deste modo, daremos conta da forma como as disposicoes migratorias se constroem atraves dos percursos biograficos, ressaltando as potencialidades heuristicas da escala individual de observacao.

A decisão de emigrar : um estudo a partir da perspetiva da pluralidade

This paper analyses the Portuguese high-skilled emigration, focusing on the emigration decision-making process. This article aims to understand the dispositions leading to this decision, and the social processes that explain its origin, sedimentation and activation. To this end, and using the theoretical and methodological approach of Bernard Lahire, 53 sociological portraits of skilled Portuguese who emigrated to other European countries are cross-sectional analyzed. This analysis is supplemented by data from a survey previously administered. Thus, we will address how the migratory dispositions are built through the individual biographies, highlighting the heuristic potential of the individual observation scale.Este artigo analisa a emigracao portuguesa qualificada, focando-se sobre a producao da decisao de emigrar. E seu objetivo compreender as disposicoes que conduzem a essa decisao, bem como os processos sociais que explicam a sua genese, sedimentacao e ativacao. Para isso, e recorrendo a proposta teorica e metodologica de Bernard Lahire, procede-se a analise transversal de 53 retratos sociologicos de portugueses qualificados que emigraram para outros paises europeus, complementada pelos dados de um inquerito administrado previamente. Deste modo, daremos conta da forma como as disposicoes migratorias se constroem atraves dos percursos biograficos, ressaltando as potencialidades heuristicas da escala individual de observacao.

A decisão de emigrar: um estudo a partir da perspetiva da pluralidade disposicional

This paper analyses the Portuguese high-skilled emigration, focusing on the emigration decision-making process. This article aims to understand the dispositions leading to this decision, and the social processes that explain its origin, sedimentation and activation. To this end, and using the theoretical and methodological approach of Bernard Lahire, 53 sociological portraits of skilled Portuguese who emigrated to other European countries are cross-sectional analyzed. This analysis is supplemented by data from a survey previously administered. Thus, we will address how the migratory dispositions are built through the individual biographies, highlighting the heuristic potential of the individual observation scale.Este artigo analisa a emigracao portuguesa qualificada, focando-se sobre a producao da decisao de emigrar. E seu objetivo compreender as disposicoes que conduzem a essa decisao, bem como os processos sociais que explicam a sua genese, sedimentacao e ativacao. Para isso, e recorrendo a proposta teorica e metodologica de Bernard Lahire, procede-se a analise transversal de 53 retratos sociologicos de portugueses qualificados que emigraram para outros paises europeus, complementada pelos dados de um inquerito administrado previamente. Deste modo, daremos conta da forma como as disposicoes migratorias se constroem atraves dos percursos biograficos, ressaltando as potencialidades heuristicas da escala individual de observacao.