Forebrain Deletion of αGDI in Adult Mice Worsens the Pre-Synaptic Deficit at Cortico-Lateral Amygdala Synaptic Connections

Veronica Bianchi,Daniela Toniolo,Yann Humeau,Frédéric Gambino,Patrizia D'Adamo,Luca Muzio,Judith Homberg

doi:10.1371/journal.pone.0029763

Abstract

The GDI1 gene encodes αGDI, which retrieves inactive GDP-bound RAB from membranes to form a cytosolic pool awaiting vesicular release. Mutations in GDI1 are responsible for X-linked Intellectual Disability. Characterization of the Gdi1-null mice has revealed alterations in the total number and distribution of hippocampal and cortical synaptic vesicles, hippocampal short-term synaptic plasticity and specific short-term memory deficits in adult mice, which are possibly caused by alterations of different synaptic vesicle recycling pathways controlled by several RAB GTPases. However, interpretation of these studies is complicated by the complete ablation of Gdi1 in all cells in the brain throughout development. In this study, we generated conditionally gene-targeted mice in which the knockout of Gdi1 is restricted to the forebrain, hippocampus, cortex and amygdala and occurs only during postnatal development. Adult mutant mice reproduce the short-term memory deficit previously reported in Gdi1-null mice. Surprisingly, the delayed ablation of Gdi1 worsens the pre-synaptic phenotype at cortico-amygdala synaptic connections compared to Gdi1-null mice. These results suggest a pivotal role of αGDI via specific RAB GTPases acting specifically in forebrain regions at the pre-synaptic sites involved in memory formation.

Highlights

Human intellectual disability (ID), referred to as Mental Retardation (MR), is a common human neurodevelopment disorder with onset early in postnatal life
Inactivation of aGDI occurs in specific brain regions during postnatal life To generate a conditional Gdi1 mouse model, we generated a floxed allele of Gdi1 by flanking exons 2 and 3 of the mouse Gdi1 gene with two lox P sites using homologous recombination in embryonic stem (ES) cells (Fig. 1A)
We suggested that the memory deficit might be caused by alterations in the synaptic vesicles (SV) pool and short-term synaptic plasticity involving alterations of different trafficking pathways that are controlled by several RAB GTPase proteins [6]

Summary

Introduction

Human intellectual disability (ID), referred to as Mental Retardation (MR), is a common human neurodevelopment disorder with onset early in postnatal life. This condition affects approximately 2–3% of the human population [1]. The identification and functional characterization of these genes have greatly enlarged our understanding of human cognition and intellect. Because NS-ID is characterized clinically only by intellectual impairment, the genes underlying this clinical condition are likely to be involved in learning and memory formation. The functional study of these genes might help to understand neural development and provide treatment strategies for NS-ID

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Results

Conclusion