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-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.
Bianchi
Veronica
V
Dulbecco Telethon Institute at DIBIT-San Raffaele Scientific Institute, Milan, Italy.
Farisello
Pasqualina
P
Baldelli
Pietro
P
Meskenaite
Virginia
V
Milanese
Marco
M
Vecellio
Matteo
M
Mühlemann
Sven
S
Lipp
Hans Peter
HP
Bonanno
Giambattista
G
Benfenati
Fabio
F
Toniolo
Daniela
D
D'Adamo
Patrizia
P
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*
C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors