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

<div><p>The <em>GDI1</em> gene encodes αGDI, which retrieves inactive GDP-bound RAB from membranes to form a cytosolic pool awaiting vesicular release. Mutations in <em>GDI1</em> are responsible for X-linked Intellectual Disability. Characterization of the <em>Gdi1</em>-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 <em>Gdi1</em> in all cells in the brain throughout development. In this study, we generated conditionally gene-targeted mice in which the knockout of <em>Gdi1</em> 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 <em>Gdi1</em>-null mice. Surprisingly, the delayed ablation of <em>Gdi1</em> worsens the pre-synaptic phenotype at cortico-amygdala synaptic connections compared to <em>Gdi1</em>-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.</p>