Journal Article

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

Veronica Bianchi, Pasqualina Farisello, Pietro Baldelli, Virginia Meskenaite, Marco Milanese, Matteo Vecellio, Sven Mühlemann, Hans Peter Lipp, Giambattista Bonanno, Fabio Benfenati, Daniela Toniolo and Patrizia D'Adamo

in Human Molecular Genetics

Volume 18, issue 1, pages 105-117
Published in print January 2009 | ISSN: 0964-6906
Published online October 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn321
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

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The GDI1 gene, responsible in human for X-linked non-specific mental retardation, encodes αGDI, 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 αGDI impairs several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus. Alteration of the SV reserve pool (RP) 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 RP of SVs 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.

Journal Article.  8713 words.  Illustrated.

Subjects: Genetics and Genomics

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