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The Journal of Neuroscience, November 4, 2009, 29(44):14039-14049; doi:10.1523/JNEUROSCI.2483-09.2009

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Cellular/Molecular
Inositol 1,4,5-Trisphosphate 3-Kinase A Functions As a Scaffold for Synaptic Rac Signaling

Il Hwan Kim,¹ Soon Kwon Park,³ Soon Taek Hong,¹ Yong Sang Jo,² Eun Joo Kim,² Eun Hye Park,² Seung Baek Han,¹ Hee-Sup Shin,⁴ Woong Sun,¹ Hyun Taek Kim,² Scott H. Soderling,^5,6 and Hyun Kim¹

¹Department of Anatomy, College of Medicine, Korea University, Brain Korea 21, Seoul 136-705, Korea, ²Department of Psychology, Korea University, Seoul 136-701, Korea, ³School of Alternative Medicine and Health Science, Jeonju University, Jeonju 520-759, Korea, ⁴Center for Neural Science, Korea Institute of Science and Technology, Seoul 136-791, Korea, and ⁵Departments of Cell Biology and ⁶Neurobiology, Duke University Medical School, Durham, North Carolina 27710

Correspondence should be addressed to Dr. Hyun Kim, Department of Anatomy, College of Medicine, Korea University, Seoul 136-705, Korea. Email: kimhyun{at}korea.ac.kr

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 (IP₃K-A), independent of its kinase activity. On neural activation, IP₃K-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 IP₃K-A, IP₃K-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, IP₃K-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 IP₃K-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.

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Received May 28, 2009; revised Sept. 19, 2009; accepted Sept. 22, 2009.

Correspondence should be addressed to Dr. Hyun Kim, Department of Anatomy, College of Medicine, Korea University, Seoul 136-705, Korea. Email: kimhyun{at}korea.ac.kr

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