ORIGINAL ARTICLE The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability Chun-Lei Zhang • Xander Houbaert • Marilyn Lepleux • Melissa Deshors • Elisabeth Normand • Fre ´de ´ric Gambino • Etienne Herzog • Yann Humeau Received: 11 June 2014 / Accepted: 20 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014 Abstract The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to envi- ronmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory forma- tion, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intel- lectual disability gene Il1rapl1. Functional in vivo exper- iments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbal- ance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories. Keywords Contextual fear expression Á Hippocampal projections Á Optogenetic Á Intellectual disability Introduction Learning and memory processes are crucial to adapt our behaviors to environmental cues and highly depend on the ability of discrete neuronal circuits to integrate sensory information to elicit correct behavioral responses. Geneti- cally encoded intellectual disability (ID) mostly results from mutations in genes functioning in neuronal and syn- aptic signaling cascades (Pavlowsky et al. 2011). Among these, IL1RAPL1 is a member of a novel family of IL1/Toll receptors thought to be expressed at excitatory synapses (Pavlowsky et al. 2010) and mutations in IL1RAPL1 gene have been shown to induce autism and ID in humans (Carrie ´ et al. 1999; Piton et al. 2008). At the cellular level, IL1RAPL1 is thought to be a trans-synaptic adhesion protein promoting pre- and post-synaptic effectors impor- tant for the formation, maintenance and function of excit- atory synapses (Gambino et al. 2007; Yoshida et al. 2011; Valnegri et al. 2011; Hayashi et al. 2013). At the C.-L. Zhang and X. Houbaert contributed equally to the work. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0882-x) contains supplementary material, which is available to authorized users. C.-L. Zhang Á X. Houbaert Á M. Lepleux Á M. Deshors Á E. Normand Á F. Gambino Á E. Herzog Á Y. Humeau Team Synapse in Cognition, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Universite ´ de Bordeaux, Bordeaux, France M. Deshors Á E. Normand Pole In Vivo, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Universite ´ de Bordeaux, Bordeaux, France Y. Humeau (&) UMR5297 Institut Interdisciplinaire de NeuroScience, Centre de Ge ´nomique Fonctionnelle, 146 rue Le ´o Saignat, 33077 Bordeaux Cedex, France e-mail: yann.humeau@u-bordeaux.fr 123 Brain Struct Funct DOI 10.1007/s00429-014-0882-x