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Thèse Silvia Viana Da Silva

Pathophysiology of Hippocampal CA3 Neurons in the APP/PS1 Mouse Model of Alzheimer’s Disease

Le 19 décembre 2014

Soutenance au Portugal Directeur de thèse: Dr. Christophe Mulle (Bordeaux) et Dr. Rodrigo Cunha (co-director de these)

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized clinically by progressive memory loss eventually resulting in dementia.


  We found that mossy fiber synapses (Mf) are relatively spared in transgenic animals as compared to associative-comisssural (A/C) synapses both functionally and morphologically.
The prominent Mf short-term presynaptic plasticities showed not to be affected at 6 months, and their characteristic presynaptic long-term potentiation (LTP) was also normal. Morphology analysis showed, likewise, no alterations in size of the Mf pre and postsynaptic compartments. There was although an alteration in the complexity of the Mf boutons (presynaptic) that does not correspond to a postsynaptic alteration (thorny excrescences, display similar complexity index between genotypes). This result suggests alterations of the filopodia size and/or number, and putative impairments concerning the GABAergic network. In contrast to the lack of presynaptic glutamatergic deficits at Mf synapses, we found a striking loss of NMDA receptor (NMDAR)-dependent long-term plasticity (LTP) at A/C synapses. This loss of LTP was correlated with subtle alterations of the dendritic spine morphology accompanied by a reduced spine density. Importantly, we found that the loss of postsynaptic LTP was not caused by alterations in the amount of synaptic NMDARs, since we found no alteration in NMDAR/AMPAR ratio at A/C synapses. We further exclude alterations in extrasynaptic NMDARs signaling.

On the cellular level modulations of synaptic strength as LTP and LTD are thought to be key mechanisms underlying learning and memory. The results we obtained clearly point out the importance to address the role that individual synapses play in AD with the high spatial and temporal resolution that just whole-cell patch-clamp recordings can provide. Our results also point out that, in this model, at early phase of the disease the main synaptic deficits are post-synaptic, and not presynaptic as some publications suggested. Furthermore, our data allows to understand that the chronic deposition of Aβ disturbed LTP without altering NMDARs conductance (synaptically and extrasynaptically), suggesting that the loss of LTP might be due to alterations in intracellular mechanisms downstream NMDARs.

A2A receptors (A2ARs) and metabotropic glutamate receptors 5 (mGluR5) are known to modulate NMDAR signaling and reported to be important targets for AD treatment. Furthermore, both caffeine (antagonist of A2AR) and MTEP (antagonist of mGluR5) have been reported to rescue behavioural deficits in AD mice models. We found that short application of both these drugs resulted in a partial rescue of the LTP levels in the A/C synapses of APP/PS1 animals.

Silvia Silva / University of California / San Diego Stefan Leutgeb Lab /
Dernière mise à jour le 05.09.2016

JURY

Dr. Dietmar Schmitz
Dr. Ana Cristina RegoProf.
Dr. Catarina Resende Oliveira
Dr. Rodrigo Cunha (co-director)
Dr. Christophe Mulle

Directeurs de thèse



Christophe Mulle , Université de Bordeaux IINS,  , Team leader : Physiology of glutamatergic synapses.



Rodrigo Cunha
Associate Professor
Faculty of Medecine
University of Coimbra