The insulin receptor substrate of 53 kDa (IRSp53) limits hippocampal synaptic plasticity.
IRSp53 is an essential intermediate between the activation of Rac and Cdc42 GTPases and the formation of cellular protrusions; it affects cell shape by coupling membrane-deforming activity with the actin cytoskeleton. IRSp53 is highly expressed in neurons where it is also an abundant component of the postsynaptic density (PSD). Here we analyze the physiological function of this protein in the mouse brain by generating IRSp53-deficient mice. Neurons in the hippocampus of young and adult knock-out (KO) mice do not exhibit morphological abnormalities in vivo. Conversely, primary cultured neurons derived from IRSp53 KO mice display retarded dendritic development in vitro. On a molecular level, Eps8 cooperates with IRSp53 to enhance actin bundling and interacts with IRSp53 in developing neurons. However, postsynaptic Shank proteins which are expressed at high levels in mature neurons compete with Eps8 to block actin bundling. In electrophysiological experiments the removal of IRSp53 increases synaptic plasticity as measured by augmented long term potentiation and paired-pulse facilitation. A primarily postsynaptic role of IRSp53 is underscored by the decreased size of the PSDs, which display increased levels of N-methyl-d-aspartate receptor subunits in IRSp53 KO animals. Our data suggest that the incorporation of IRSp53 into the PSD enables the protein to limit the number of postsynaptic glutamate receptors and thereby affect synaptic plasticity rather than dendritic morphology. Consistent with altered synaptic plasticity, IRSp53-deficient mice exhibit cognitive deficits in the contextual fear-conditioning paradigm.
Sawallisch
Corinna
C
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
Berhörster
Kerstin
K
Disanza
Andrea
A
Mantoani
Sara
S
Kintscher
Michael
M
Stoenica
Luminita
L
Dityatev
Alexander
A
Sieber
Sabrina
S
Kindler
Stefan
S
Morellini
Fabio
F
Schweizer
Michaela
M
Boeckers
Tobias M
TM
Korte
Martin
M
Scita
Giorgio
G
Kreienkamp
Hans-Jürgen
HJ
D000818:Animals; D002460:Cell Line; D048430:Cell Shape; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D046509:Tissue Culture Techniques
C539986:Baiap2 protein, mouse; D009419:Nerve Tissue Proteins