Multivariate Synaptic and Behavioral Profiling Reveals New Developmental Endophenotypes in the Prefrontal Cortex

Overview

Journal Sci Rep

Specialty Science

Date 2016 Oct 22

PMID 27765946

Citations 8

Authors

Jillian Iafrati

Arnaud Malvache

Cecilia Gonzalez Campo

M Juliana Orejarena

Olivier Lassalle

Lamine Bouamrane

Pascale Chavis

Affiliations

Soon will be listed here.

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.

Citing Articles

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Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases.

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