PhD: Xander Houbaert

Study of fear memory and associated synaptic mechanisms in a mouse model of intellectual disability

Defended on November 28, 2014

Intellectual disability (ID) comprises a highly heterogeneous collection of neurodevelopmental disorders that arises during childhood. They have an incidence of 1-3% in the population with patients showing impairments in mental and adaptive functions. ID-related proteins are often found enriched at synapses in the brain, exerting highly different biological functions (Bokhoven 2011, Annu. Rev. Genet.), suggesting that cognitive impairments defining ID could be related to alterations of synaptic function (Humeau et al. 2009, J.Neurochem.). Our main goal is to understand the role of these proteins in synaptic function and cognition using mice models bearing ID gene mutations. During my PhD I focused on the study of a specific ID-gene: the Interleukin-receptor-accessory-protein-like-1 or Il1rapl1. Microdeletions or mutations of this gene are directly linked to the development of ID and autism spectrum disorder in humans (Carrié et al. 1999, Nat. Genet.; Piton et al. 2008, Hum. Mol. Genet.). IL1RAPL1 encodes a transmembranous protein and several in vitro experiments point to an important role in the differentiation and stabilization of excitatory synapses trough interactions with presynaptic (Gambino et al. 2007, PNAS), trans-synaptic (Yoshida et al. 2011, J. Neurosci.) or postsynaptic partners (Pavlowsky et al. 2010, Curr. Biol.).

However, consequences of Il1rapl1 deficiency at more integrated level remains poorly understood. To answer this, I used a KO mouse model of Il1rapl1 and applied a variety of experimental approaches, ranging from behavior to cellular and neural network physiology. I could show that the mutation impacted fear memory at different levels by changing the balance between excitatory and inhibitory transmission in the brain.

Conclusion scheme : A: Il1rapl1 deficiency and synaptic function In both LA and BLA, absence of Il1rapl1 led to lower excitation reaching LA principal cells and had no effect on inhibition (interneuron in blue). This causes a local E/I imbalance in both structures. B: Il1rapl1 deficiency and fear learning In LA, E/I imbalance caused synaptic plasticity deficits that impacted the acquisition of the cued fear memory. In BLA, E/I imbalance caused lower activation of BLA principal cells during contextual re-exposure, impacting the expression of the contextual fear memory.

 

 

 Publications

Zhang CL, Houbaert X, Lepleux M, Deshors M, Normand E, Gambino F, Herzog E, Humeau Y. The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability. Brain Struct Funct. 2014 Aug 27. 2014

Jayachandran R, Liu X, Bosedasgupta S, Müller P, Zhang CL, Moshous D, Studer V, Schneider J, Genoud C, Fossoud C, Gambino F, Khelfaoui M, Müller C, Bartholdi D, Rossez H, Stiess M, Houbaert X, Jaussi R, Frey D, Kammerer RA, Deupi X, de Villartay JP, Lüthi A, Humeau Y, Pieters J. Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling. PLoS Biol. 2014 Mar 25;12(3):e1001820. 2014

Jayachandran R, Liu X, Bosedasgupta S, Müller P, Zhang CL, Moshous D, Studer V, Schneider J, Genoud C, Fossoud C, Gambino F, Khelfaoui M, Müller C, Bartholdi D, Rossez H, Stiess M, Houbaert X, Jaussi R, Frey D, Kammerer RA, Deupi X, de Villartay JP, Lüthi A, Humeau Y, Pieters J. Coronin 1 Regulates Cognition and Behavior through Modulation of cAMP/Protein Kinase A Signaling. PLoS Biol. 2014 Mar 25;12(3):e1001820. 2014

Khelfaoui M, Gambino F, Houbaert X, Ragazzon B, Müller C, Carta M, Lanore F, Srikumar BN, Gastrein P, Lepleux M, Zhang CL, Kneib M, Poulain B, Reibel-Foisset S, Vitale N, Chelly J, Billuart P, Lüthi A, Humeau Y. Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway. Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2;369(1633):20130160. 2013

Houbaert X, Zhang CL, Gambino F, Lepleux M, Deshors M, Normand E, Levet F, Ramos M, Billuart P, Chelly J, Herzog E, Humeau Y. Target-Specific Vulnerability of Excitatory Synapses Leads to Deficits in Associative Memory in a Model of Intellectual Disorder. J Neurosci. 2013 Aug 21;33(34):13805-13819.. 2013

Committee

  • Bertrand Lambolez
    DR CNRS  – Rapporteur
  • Nael Nadif Kasri
    Associate  – professor – Rapporteur
  • Cyril Herry
    CR Inserm – Examinateur
  • Carlo Sala
    Senior Researcher – Examinateur

PhD supervisor

Yann Humeau

Tenured CNRS Investigator
Team Leader : Synapse in cognition – Interdisciplinary Institute for Neuroscience (IINS)

Last update: 10 April 2018