Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

• DOI: 10.1523/jneurosci.4306-08.2009
• Publication Date: 2009-02-04T18:33:35Z
• Authors: Myoung-Hwan Kim; Jeonghoon Choi; Jinhee Yang; Woosuk Chung; Ji-Hyun Kim; Sang Kyoo Paik; Karam Kim; Seungnam Han; Hyejung Won; Young-Soo Bae; Suk-Hee Cho; Jinsoo Seo; Yong Chul Bae; Se-Young Choi; Eunjoon Kim
• Keywords: Male; 0301 basic medicine; Memory Disorders; 571; Long-Term Potentiation; DENDRITIC SPINE MORPHOGENESIS; INSULIN-RECEPTOR; POSTSYNAPTIC DENSITY; ACTIN DYNAMICS; SUBSTRATE P53; EXCITATORY SYNAPSES; HOMOLOGY DOMAIN; MEMBRANE; PROTEIN; CDC42; Mice, Transgenic; Nerve Tissue Proteins; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Rats; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Memory; Animals; Learning

IRSp53 is an adaptor protein that acts downstream of Rac and Cdc42 small GTPases and is implicated in the regulation of membrane deformation and actin filament assembly. In neurons, IRSp53 is an abundant postsynaptic protein and regulates actin-rich dendritic spines; however, itsin vivofunctions have not been explored. We characterized transgenic mice deficient of IRSp53 expression. Unexpectedly, IRSp53−/−neurons do not show significant changes in the density and ultrastructural morphologies of dendritic spines. Instead, IRSp53−/−neurons exhibit reduced AMPA/NMDA ratio of excitatory synaptic transmission and a selective increase in NMDA but not AMPA receptor-mediated transmission. IRSp53−/−hippocampal slices show a markedly enhanced long-term potentiation (LTP) with no changes in long-term depression. LTP-inducing theta burst stimulation enhances NMDA receptor-mediated transmission. Spatial learning and novel object recognition are impaired in IRSp53−/−mice. These results suggest that IRSp53 is involved in the regulation of NMDA receptor-mediated excitatory synaptic transmission, LTP, and learning and memory behaviors.