Target-specific vulnerability of excitatory synapses leads to deficits in associative memory in a model of intellectual disorder

• Published in: The Journal of neuroscience 2013-08, Vol.33 (34), p.13805-13819
• Main Authors: Houbaert, Xander, Zhang, Chun-Lei, Gambino, Frédéric, Lepleux, Marilyn, Deshors, Melissa, Normand, Elisabeth, Levet, Florian, Ramos, Mariana, Billuart, Pierre, Chelly, Jamel, Herzog, Etienne, Humeau, Yann
• Format: Article
• Language: English
• Subjects: Amygdala - cytology; Anesthetics, Local - pharmacology; Animals; Association Learning - physiology; Cerebral Cortex - cytology; Channelrhodopsins; Conditioning (Psychology) - physiology; Dendritic Spines - metabolism; Dendritic Spines - ultrastructure; Disease Models, Animal; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - genetics; Excitatory Postsynaptic Potentials - physiology; Fear - physiology; GABA Antagonists - pharmacology; Glutamate Decarboxylase - genetics; Green Fluorescent Proteins - genetics; In Vitro Techniques; Intellectual Disability - complications; Intellectual Disability - genetics; Interleukin-1 Receptor Accessory Protein - genetics; Interleukin-1 Receptor Accessory Protein - metabolism; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Male; Memory Disorders - etiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins - metabolism; Neural Inhibition - drug effects; Neural Inhibition - genetics; Neurons - physiology; Neurons - ultrastructure
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.1457-13.2013

Intellectual disorders (IDs) have been regularly associated with morphological and functional deficits at glutamatergic synapses in both humans and rodents. How these synaptic deficits may lead to the variety of learning and memory deficits defining ID is still unknown. Here we studied the functional and behavioral consequences of the ID gene il1rapl1 deficiency in mice and reported that il1rapl1 constitutive deletion alters cued fear memory formation. Combined in vivo and in vitro approaches allowed us to unveil a causal relationship between a marked inhibitory/excitatory (I/E) imbalance in dedicated amygdala neuronal subcircuits and behavioral deficits. Cell-targeted recordings further demonstrated a morpho-functional impact of the mutation at thalamic projections contacting principal cells, whereas the same afferents on interneurons are unaffected by the lack of Il1rapl1. We thus propose that excitatory synapses have a heterogeneous vulnerability to il1rapl1 gene constitutive mutation and that alteration of a subset of excitatory synapses in neuronal circuits is sufficient to generate permanent cognitive deficits.