Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning.
Dendritic spines are dynamic, actin-rich structures that form the postsynaptic sites of most excitatory synapses in the brain. The F-actin severing protein cofilin has been implicated in the remodeling of dendritic spines and synapses under normal and pathological conditions, by yet unknown mechanisms. Here we report that β-arrestin-2 plays an important role in NMDA-induced remodeling of dendritic spines and synapses via translocation of active cofilin to dendritic spines. NMDAR activation triggers cofilin activation through calcineurin and phosphatidylinositol 3-kinase (PI3K)-mediated dephosphorylation and promotes cofilin translocation to dendritic spines that is mediated by β-arrestin-2. Hippocampal neurons lacking β-arrestin-2 develop mature spines that fail to remodel in response to NMDA. β-Arrestin-2-deficient mice exhibit normal hippocampal long-term potentiation, but significantly impaired NMDA-dependent long-term depression and spatial learning deficits. Moreover, β-arrestin-2-deficient hippocampal neurons are resistant to Aβ-induced dendritic spine loss. Our studies demonstrate unique functions of β-arrestin-2 in NMDAR-mediated dendritic spine and synapse plasticity through spatial control over cofilin activation.
Division of Biomedical Sciences, Neuroscience Graduate Program, and Developmental Biology Graduate Program, University of California, Riverside, CA 92521, USA.
Crystal G
CG
Pontrello
Min-Yu
MY
Sun
Alice
A
Lin
Todd A
TA
Fiacco
Kathryn A
KA
DeFea
Iryna M
IM
Ethell
D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000818:Animals; D019390:Arrestins / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology*; D007858:Learning; D036881:Long-Term Synaptic Depression; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
D051339:Actin Depolymerizing Factors; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D016194:Receptors, N-Methyl-D-Aspartate; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016202:N-Methylaspartate; D019869:Phosphatidylinositol 3-Kinases; D019703:Calcineurin