title: Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway.
abstract: Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure-resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists.
authors.affiliation: 1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de Recherche 901, Marseille, France [3] INMED, Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Iafrati
authors.affiliation: 1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de Recherche 901, Marseille, France [3] INMED, Marseille, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Orejarena
authors.affiliation: 1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de Recherche 901, Marseille, France [3] INMED, Marseille, France.
authors.forename: O
authors.initials: O
authors.lastname: Lassalle
authors.affiliation: 1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de Recherche 901, Marseille, France [3] INMED, Marseille, France.
authors.forename: L
authors.initials: L
authors.lastname: Bouamrane
authors.forename: C
authors.initials: C
authors.lastname: Gonzalez-Campo
authors.affiliation: 1] INSERM UMR 901, Marseille, France [2] Aix-Marseille Université, Unité Mixte de Recherche 901, Marseille, France [3] INMED, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Chavis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency / Q000235:genetics*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics*; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010636:Phenols; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018683:Excitatory Amino Acid Agents; D016326:Extracellular Matrix Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C109643:Ro 25-6981; D007649:Ketamine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D020123:Sirolimus