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BBB seminar: Hiroyuki Okuno

Role of Arc/arg3.1 in regulation of AMPA receptor dynamics and in behavioral flexibility

Hiroyuki Okuno
Department of Biochemistry and Molecular Biology, Kagoshima University School of Medicine, Kagoshima, Japan 

The neuronal immediate early gene Arc/arg3.1 is one of the most dynamically regulated genes in response to various types of extracellular stimuli in neurons. The protein product Arc is a postsynaptic protein and plays critical roles in synaptic plasticity and homeostatic scaling. We previously proposed the inverse synaptic tagging mechanism of Arc for synapse-specific AMPA-type glutamate receptor (AMPA-R) regulation. However, the exact AMPA-R dynamics associated with Arc-mediated inverse tagging remains unknown. To address this issue, we developed a live imaging system that enabled us to record subunit-specific AMPA-R lateral diffusion during structural plasticity in Arc-knockout (Arc-KO) and wildtype (WT) in cultured hippocampal neurons. We found that long-term potentiation (LTP) of surface GluA1/GluA2 levels in spines with volume expansion was undistinguishable between WT and Arc-KO neurons. Interestingly, surface GluA1/GluA2 complex gradually decreased in non-expanding spines of WT neurons during the late phase of structural plasticity, and this effect was abolished in Arc-KO neurons, being consistent with the inverse tagging of Arc to weak synapses. Furthermore, as proposed by a theoretical prediction, Arc-KO mice showed specific behavioral abnormality in behavioral flexibility tasks. Detailed analysis of behavior during the tasks revealed a deficit in task switching in Arc-KO mice. Taken together, our findings suggest a novel synaptic mechanism by which Arc expression regulates executive function including cognitive flexibility.

Chairperson: Clive Bramham, Department of Biomedicine