Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin-Related Protein 2-3 Complex / antagonists & inhibitors*
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Actin-Related Protein 2-3 Complex / metabolism
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Animals
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Animals, Newborn
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cells, Cultured
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Cytoskeletal Proteins
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Dendritic Spines / drug effects
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Dendritic Spines / metabolism
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Dendritic Spines / physiology*
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Embryo, Mammalian
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Neuronal Plasticity* / drug effects
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Neuronal Plasticity* / genetics
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Neuronal Plasticity* / physiology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / physiology
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Organelle Size / drug effects
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Organelle Size / physiology
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RNA, Small Interfering / pharmacology
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Rats
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Rats, Wistar
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Receptors, N-Methyl-D-Aspartate / metabolism
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Receptors, N-Methyl-D-Aspartate / physiology
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Synapses / drug effects
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Synapses / metabolism
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Synapses / physiology*
Substances
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Actin-Related Protein 2-3 Complex
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Carrier Proteins
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Cytoskeletal Proteins
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Nuclear Proteins
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PICK1 protein, rat
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RNA, Small Interfering
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Receptors, N-Methyl-D-Aspartate