title: 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.
abstract: The GDI1 gene, responsible in human for X-linked non-specific mental retardation, encodes alphaGDI, 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 alphaGDI 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.
authors.affiliation: Dulbecco Telethon Institute at DIBIT-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Farisello
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.forename: Virginia
authors.initials: V
authors.lastname: Meskenaite
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Matteo
authors.initials: M
authors.lastname: Vecellio
authors.forename: Sven
authors.initials: S
authors.lastname: Mühlemann
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Lipp
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
mesh_terms: D000818:Animals; D003071:Cognition; D005260:Female; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007858:Learning; D008297:Male; D008568:Memory; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D013572:Synaptic Vesicles / Q000235:genetics / Q000502:physiology*
chemical_list: C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors