p140Cap regulates memory and synaptic plasticity through Src-mediated and citron-N-mediated actin reorganization.
A major challenge in the neuroscience field is the identification of molecules and pathways that control synaptic plasticity and memory. Dendritic spines play a pivotal role in these processes, as the major sites of excitatory synapses in neuronal communication. Previous studies have shown that the scaffold protein p140Cap localizes into dendritic spines and that its knockdown negatively modulates spine shape in culture. However, so far, there is no information on its in vivo relevance. By using a knock-out mouse model, we here demonstrate that p140Cap is a key element for both learning and synaptic plasticity. Indeed, p140Cap(-/-) mice are impaired in object recognition test, as well as in LTP and in LTD measurements. The in vivo effects of p140Cap loss are presumably attenuated by noncell-autonomous events, since primary neurons obtained from p140Cap(-/-) mice show a strong reduction in number of mushroom spines and abnormal organization of synapse-associated F-actin. These phenotypes are most likely caused by a local reduction of the inhibitory control of RhoA and of cortactin toward the actin-depolymerizing factor cofilin. These events can be controlled by p140Cap through its capability to directly inhibit the activation of Src kinase and by its binding to the scaffold protein Citron-N. Altogether, our results provide new insight into how protein associated with dynamic microtubules may regulate spine actin organization through interaction with postsynaptic density components.
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, Department of Neuroscience, University of Torino, 10126 Torino, Italy, Institute of Neuroscience of the National Research Council of Italy, 56124 Pisa, Italy, Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, 50135 Florence, Italy, National Institute of Neuroscience-Italy, 10125 Torino, Italy, Department of Biotechnology and Translational Medicine, University of Milan, and Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy, and Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, D-48149 Münster, Germany.
Daniele
D
Repetto
Paola
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Camera
Riccardo
R
Melani
Noemi
N
Morello
Isabella
I
Russo
Eleonora
E
Calcagno
Romana
R
Tomasoni
Federico
F
Bianchi
Gaia
G
Berto
Maurizio
M
Giustetto
Nicoletta
N
Berardi
Tommaso
T
Pizzorusso
Michela
M
Matteoli
Paola
P
Di Stefano
Markus
M
Missler
Emilia
E
Turco
Ferdinando
F
Di Cunto
Paola
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Defilippi
D000199:Actins / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D000199:Actins; D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; C000631270:Srcin1 protein, rat; C115635:citron-kinase; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases
Cit-N; Rho GTPase; Src; actin cytoskeleton; p140Cap; synapses