Human Molecular Genetics Advance Access published online on October 1, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn321
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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
1 Dulbecco Telethon Institute at DIBIT-San Raffaele Scientific Institute, Milan, Italy 2 Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, and Department of Experimental Medicine, Section of Physiology, University of Genoa and Italian Institute of Neuroscience, Genoa, Italy 3 Institute of Anatomy, University of Zurich, Zurich, Switzerland 4 Department of Experimental Medicine, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy 5 Genetics of Common Disorders Unit, DIBIT-San Raffaele Scientific Institute, Milan, Italy
* Corresponding author: Patrizia D'Adamo, Dulbecco Telethon Institute, Molecular Genetic of Mental Retardation Unit, at DIBIT-San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. Tel: +39 02 26434935; Fax: +39 02 26434767; E-mail: p.dadamo{at}hsr.it
Received July 28, 2008; Revised September 30, 2008; Accepted September 30, 2008
The GDI1 gene, responsible in human for X-linked non-specific mental retardation (XLMR), encodes 
GDI, a regulatory protein common to all GTPases of the Rab family. Its alteration, leading to membrane accumulation of different Rab GTPases, may affect multiple steps in neuronal intracellular traffic. Using electron microscopy and electrophysiology, we now report that lack of GDI impairs several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus. Alteration of the SV reserve pool and a 50% reduction in the total number of SV in adult synapses may be dependent on a defective endosomal dependent recycling and 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-conditioning protocols with short intervals between trials, disappeared when the Gdi1 mutants were allowed to have longer intervals between sessions. Likewise, previously observed deficits in radial maze learning could be corrected by providing less challenging pre-training. This implies that an intact reserve pool of synaptic vesicles is necessary for memory processing under challenging conditions in mice. The possibility to correct the learning deficit in mice may have clinical implication for future studies in human.
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