PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity.
Activity-dependent remodelling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the precise molecular mechanisms that regulate this process are unclear. Activators of Arp2/3-mediated actin polymerisation are required for spine enlargement; however, during long-term depression (LTD), spines shrink via actin depolymerisation and Arp2/3 inhibitors in this process have not yet been identified. Here, we show that PICK1 regulates spine size in hippocampal neurons via inhibition of the Arp2/3 complex. PICK1 knockdown increases spine size, whereas PICK1 overexpression reduces spine size. NMDA receptor activation results in spine shrinkage, which is blocked by PICK1 knockdown or overexpression of a PICK1 mutant that cannot bind Arp2/3. Furthermore, we show that PICK1-Arp2/3 interactions are required for functional hippocampal LTD. This work demonstrates that PICK1 is a novel regulator of spine dynamics. Via Arp2/3 inhibition, PICK1 has complementary yet distinct roles during LTD to regulate AMPA receptor trafficking and spine size, and therefore functions as a crucial factor in both structural and functional plasticity.
MRC Centre for Synaptic Plasticity, School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
Yasuko
Y
Nakamura
Catherine L
CL
Wood
Andrew P
AP
Patton
Nadia
N
Jaafari
Jeremy M
JM
Henley
Jack R
JR
Mellor
Jonathan G
JG
Hanley
D051376:Actin-Related Protein 2-3 Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053141:Organelle Size / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D051376:Actin-Related Protein 2-3 Complex; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate
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