Brain phenotype of transgenic mice overexpressing cystathionine β-synthase.

Vinciane Régnier,David Patterson,Sapna Gupta,Guido Vacano,Brigitte Potier,Jean-Charles Bizot,Sabrina Luilier,Jean M Delabar,Jan P Kraus,Stéphanie Woerner,Jean-Marie Billard,Jaqueline London,Evelyne Paly,Aurélie Ledru,Sabrina David,Warren D Kruger

doi:10.1371/journal.pone.0029056

Abstract

BackgroundThe cystathionine β-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes.Methodology/Principal FindingsHere, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ∼2-fold increase in total CBS proteins in different brain areas and a ∼1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line.Conclusion/SignificanceWe demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS.

Highlights

Down syndrome (DS) is a genomic disorder, caused by total or partial trisomy of human chromosome 21 (Hsa21), which occurs in about 1/800 live births [1]
We found a mean value of 1.0260.03, indicating that 2 copies of the cystathionine b-synthase (CBS)-bearing human genomic fragment were integrated in the 60.4P102D1 line
We examined amino acid levels related to sulfur-containing amino acid (SAA) metabolism in the hippocampi of transgenic and control animals, but the small quantities of material required us to pool the hippocampi of each group together for analysis

Summary

Introduction

Down syndrome (DS) is a genomic disorder, caused by total or partial trisomy of human chromosome 21 (Hsa21), which occurs in about 1/800 live births [1]. Penetrance and expressivity of DS phenotypic traits are highly variable in affected people. Intellectual disability (ID) is one of the few phenotypes with full penetrance, its intensity can vary from severe to moderate (IQ = 25–55) [3]. The cystathionine b-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes

Methods

Results

Conclusion