PhD: Senka Hadzibegovic

Behavioral, molecular and electrophysiological characterization of the learning and memory deficits induced in mouse models of Alzheimer’s disease

Defended on September 10, 2015

Equipe de Bruno Bontempi : Dynamique des réseaux neuronaux et vasculaires dans les processus mnésiques.

Summary

Cognitive impairments in Alzheimer’s disease (AD) are thought to be related to degenerative synaptic changes caused by the accumulation of amyloid-β peptides (Aβs) in vulnerable brain regions such as the hippocampus. At the molecular level, Aβs bind preferentially to the postsynaptic density of neuronal excitatory synapses, where the scaffolding post-synaptic protein-95 (PSD-95) organizes NMDA receptor (NMDAR) location as well as its downstream signaling.

By using an integrative strategy which favoured vertical levels of analyses (from phenotype to molecular events) and combined a set of interrelated correlative and invasive approaches in a double transgenic mouse model of AD (APPswe/PS1dE9 mice), we were successful in establishing that Aβs destabilize the synaptic organization (reduction of expression of PSD-95) and increase the extrasynaptic pool of GluN2B-containing NMDAR in the hippocampus, a reorganization which translates into impaired memory functions. It is also well-known that hippocampal sharp wave-ripples (SWRs) generated during sleep periods are crucial for memory formation but accumulation of soluble Aβs, surprisingly seems to spare SWR dynamics during routine behavior.

To unravel a potential effect of Aβs on SWRs in cognitively-challenged animals, we submitted vehicle- and Aβ-injected mice to spatial recognition memory testing. While capable of forming short-term memory, Aβ mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information.

Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and -recognition peaks in SWR occurrence observed in controls were abolished in Aβ mice, indicating impaired hippocampal processing of spatial information. Altogether these results identify two new disruptive mechanisms for the spatial memory deficits associated with AD.

Keywords: spatial memory, NMDA receptors, Alzheimer’s disease, hippocampal oscillations, transgenic mice

 

Publications
• O.Nicole*, S.Hadzibegovic*, J.Gajda, B.Bontempi, T. Bem, P. Meyrand. Alterations of learning-induced hippocampal ripples in a mouse model of Alzheimer’s disease impair spatial memory formation. (submitted) *Contributed equally

• K.Ilic, S.Hadzibegovic, B.Djordjevic. Relevance of some nutrients in the prevention and treatment of hypertension. Hrana i Ishrana 2011; 52 (1): 15-22.

 

Jury

Mme VERRET Laure, Maitre de conférences à l’Université de Toulouse,
M. FRERET Thomas, Professeur à l’Université de Caen,
M. BILLARD Jean-Marie, Directeur de Recherche INSERM,
M. MICHEAU Jacques, Professeur à l’université de Bordeaux.
Supervisors
M. BONTEMPI Bruno, Directeur de recherche CNRS,
M. NICOLE Olivier, Chargé de recherche CNRS

Directeur de thèse



Bruno Bontempi
Team leader: Dynamics of neuronal and vascular network in memory process
Affiliated with the lab: Neurodegenerative Diseases Institute – Erwan Bezard

 

Publications

Last update: 9 April 2018