title: Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex.
abstract: The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders.
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Jillian
authors.initials: J
authors.lastname: Iafrati
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Malvache
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gonzalez Campo
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: Orejarena
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lassalle
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Lamine
authors.initials: L
authors.lastname: Bouamrane
authors.affiliation: INSERM, 13009 Marseille, France; INMED UMR S 901, 13009 Marseille, France; Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Chavis
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases