Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training

The GDI1 gene, responsible in human for X-linked non-specificmental retardation, encodes GDI, a regulatory protein commonto all GTPases of the Rab family. Its alteration, leading tomembrane accumulation of different Rab GTPases, may affect multiplesteps in neuronal intracellular traffic. Using electron microscopyand electrophysiology, we now report that lack of GDI impairsseveral steps in synaptic vesicle (SV) biogenesis and recyclingin the hippocampus. Alteration of the SV reserve pool (RP) anda 50% reduction in the total number of SV in adult synapsesmay be dependent on a defective endosomal-dependent recyclingand may lead to the observed alterations in short-term plasticity.As predicted by the synaptic characteristics of the mutant mice,the short-term memory deficit, observed when using fear-conditioningprotocols with short intervals between trials, disappeared whenthe Gdi1 mutants were allowed to have longer intervals betweensessions. Likewise, previously observed deficits in radial mazelearning could be corrected by providing less challenging pre-training.This implies that an intact RP of SVs is necessary for memoryprocessing under challenging conditions in mice. The possibilityto correct the learning deficit in mice may have clinical implicationfor future studies in human.