title: Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability.
abstract: The grik2 gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2⁻/⁻). In GluK2⁻/⁻ mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2⁻/⁻ mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.
authors.affiliation: Interdisciplinary Institute for Neuroscience, University of Bordeaux, and  CNRS UMR 5297, F-33000 Bordeaux, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lanore
authors.forename: Virginie F
authors.initials: VF
authors.lastname: Labrousse
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szabo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Normand
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanchet
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D016202:N-Methylaspartate / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000473:pathology; D018092:Kainic Acid Receptors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000473:pathology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D000097806:GluK2 Kainate Receptor
chemical_list: D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000097806:GluK2 Kainate Receptor