Inositol 1,4,5-trisphosphate 3-kinase a functions as a scaffold for synaptic Rac signaling.
Activity-dependent alterations of synaptic contacts are crucial for synaptic plasticity. The formation of new dendritic spines and synapses is known to require actin cytoskeletal reorganization specifically during neural activation phases. Yet the site-specific and time-dependent mechanisms modulating actin dynamics in mature neurons are not well understood. In this study, we show that actin dynamics in spines is regulated by a Rac anchoring and targeting function of inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A), independent of its kinase activity. On neural activation, IP(3)K-A bound directly to activated Rac1 and recruited it to the actin cytoskeleton in the postsynaptic area. This focal targeting of activated Rac1 induced spine formation through actin dynamics downstream of Rac signaling. Consistent with the scaffolding role of IP(3)K-A, IP(3)K-A knock-out mice exhibited defects in accumulation of PAK1 by long-term potentiation-inducing stimulation. This deficiency resulted in a reduction in the reorganization of actin cytoskeletal structures in the synaptic area of dentate gyrus. Moreover, IP(3)K-A knock-out mice showed deficits of synaptic plasticity in perforant path and in hippocampal-dependent memory performances. These data support a novel model in which IP(3)K-A is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism.
Kim
Il Hwan
IH
Department of Anatomy, College of Medicine, Korea University, Brain Korea 21, Seoul, Korea.
Park
Soon Kwon
SK
Hong
Soon Taek
ST
Jo
Yong Sang
YS
Kim
Eun Joo
EJ
Park
Eun Hye
EH
Han
Seung Baek
SB
Shin
Hee-Sup
HS
Sun
Woong
W
Kim
Hyun Taek
HT
Soderling
Scott H
SH
Kim
Hyun
H
D000818:Animals; D006367:HeLa Cells; D006801:Humans; D008297:Male; D045170:Matrix Attachment Regions / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D020830:rac1 GTP-Binding Protein