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

被引:43
作者
Bianchi, Veronica
Farisello, Pasqualina [2 ,3 ,5 ]
Baldelli, Pietro [2 ,3 ,5 ]
Meskenaite, Virginia [6 ]
Milanese, Marco [4 ]
Vecellio, Matteo
Muhlemann, Sven [6 ]
Lipp, Hans Peter [6 ]
Bonanno, Giambattista [4 ]
Benfenati, Fabio [2 ,3 ,5 ]
Toniolo, Daniela [7 ]
D'Adamo, Patrizia [1 ]
机构
[1] Ist Sci San Raffaele, DIBIT, Mol Genet Mental Retardat Unit, Dulbecco Telethon Inst, I-20132 Milan, Italy
[2] Univ Genoa, Dept Neurosci & Brain Technol, Italian Inst Technol, Genoa, Italy
[3] Univ Genoa, Physiol Sect, Dept Expt Med, Genoa, Italy
[4] Univ Genoa, Dept Expt Med, Sect Pharmacol & Toxicol, Genoa, Italy
[5] Italian Inst Neurosci, Genoa, Italy
[6] Univ Zurich, Inst Anat, Zurich, Switzerland
[7] Ist Sci San Raffaele, DIBIT, Genet Common Disorders Unit, I-20132 Milan, Italy
基金
瑞士国家科学基金会;
关键词
ENDOCYTIC PATHWAYS; MENTAL-RETARDATION; GLUTAMATE RELEASE; RAB3A; ENDOSOMES; MEMBRANE; MEMORY; INVOLVEMENT; TRAFFICKING; MECHANISMS;
D O I
10.1093/hmg/ddn321
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The GDI1 gene, responsible in human for X-linked non-specific mental retardation, encodes alpha 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 alpha GDI 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.
引用
收藏
页码:105 / 117
页数:13
相关论文
共 44 条
[21]   Trial and intertrial durations in pavlovian conditioning: issues of learning and performance [J].
Lattal, KM .
JOURNAL OF EXPERIMENTAL PSYCHOLOGY-ANIMAL BEHAVIOR PROCESSES, 1999, 25 (04) :433-450
[22]   rab4 regulates transport to the apical plasma membrane in Madin-Darby canine kidney cells [J].
Mohrmann, K ;
Leijendekker, R ;
Gerez, L ;
van der Sluijs, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (12) :10474-10481
[23]   The presynaptic active zone protein RIM1α is critical for normal learning and memory [J].
Powell, CM ;
Schoch, S ;
Monteggia, L ;
Barrot, M ;
Matos, MF ;
Feldmann, N ;
Südhof, TC ;
Nestler, EJ .
NEURON, 2004, 42 (01) :143-153
[24]   Multiple mechanisms of transmitter release evoked by 'pathologically' elevated extracellular [K+]:: involvement of transporter reversal and mitochondrial calcium [J].
Raiteri, L ;
Stigliani, S ;
Zedda, L ;
Raiteri, M ;
Bonanno, G .
JOURNAL OF NEUROCHEMISTRY, 2002, 80 (04) :706-714
[25]   Mechanisms of glutamate release elicited in rat cerebrocortical nerve endings by 'pathologically' elevated extraterminal K+ concentrations [J].
Raiteri, Luca ;
Zappettini, Simona ;
Milanese, Marco ;
Fedele, Ernesto ;
Raiteri, Maurizio ;
Bonanno, Giambattista .
JOURNAL OF NEUROCHEMISTRY, 2007, 103 (03) :952-961
[26]   The genetics of mental retardation [J].
Raymond, F. Lucy ;
Tarpey, Patrick .
HUMAN MOLECULAR GENETICS, 2006, 15 :R110-R116
[27]   Kiss-and-run, collapse and 'Readily Retrievable' vesicles [J].
Rizzoli, Silvio O. ;
Jahn, Reinhard .
TRAFFIC, 2007, 8 (09) :1137-1144
[28]   Synaptic vesicle pools [J].
Rizzoli, SO ;
Betz, WJ .
NATURE REVIEWS NEUROSCIENCE, 2005, 6 (01) :57-69
[29]   STEREOLOGY - A METHOD FOR ANALYZING IMAGES [J].
ROYET, JP .
PROGRESS IN NEUROBIOLOGY, 1991, 37 (05) :433-474
[30]   Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3 [J].
Sakane, Ayuko ;
Manabe, Shinji ;
Ishizaki, Hiroyoshi ;
Tanaka-Okamoto, Miki ;
Kiyokage, Emi ;
Toida, Kazunori ;
Yoshida, Takayuki ;
Miyoshi, Jun ;
Kamiya, Haruyuki ;
Takai, Yoshimi ;
Sasaki, Takuya .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (26) :10029-10034