| First Author | Bobsin K | Year | 2015 |
| Journal | J Neurochem | PubMed ID | 26560964 |
| Mgi Jnum | J:231100 | Mgi Id | MGI:5766853 |
| Doi | 10.1111/jnc.13428 | Citation | Bobsin K, et al. (2015) Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor dependent signal transduction. J Neurochem |
| abstractText | Learning and memory is dependent on postsynaptic architecture and signaling processes in forebrain regions. The insulin receptor substrate protein of 53 kDa (IRSp53, also known as Baiap2) is a signaling and adapter protein in forebrain excitatory synapses. Mice deficient in IRSp53 display enhanced levels of postsynaptic N-methyl-D-aspartate receptors (NMDARs) and long-term potentiation (LTP) associated with severe learning deficits. In humans, reduced IRSp53/Baiap2 expression is associated with a variety of neurological disorders including autism, schizophrenia and Alzheimer's disease. Here we analyzed mice lacking one copy of the gene coding for IRSp53 using behavioural tests including contextual fear conditioning and the puzzle box. We show that a 50% reduction in IRSp53 levels strongly affects the performance in fear-evoking learning paradigms. This correlates with increased targeting of NMDARs to the postsynaptic density (PSD) in hippocampi of both heterozygous and knock out (ko) mice at the expense of extrasynaptic NMDARs. As hippocampal NMDAR dependent LTP is enhanced in IRSp53-deficient mice, we investigated signaling cascades important for the formation of fear evoked memories. Here we observed a dramatic increase in cAMP response element-binding protein (CREB) dependent signaling in heterozygous and IRSp53 deficient mice, necessary for the transcriptional dependent phase of LTP. In contrast, activation of the mitogen-activated protein (MAP) kinase and Akt kinase pathways required for translation dependent phase of LTP are reduced. Our data suggest that loss or even the reduction of IRSp53 increases NMDAR dependent CREB activation in the hippocampus, and interferes with the ability of mice to learn upon anxiety-related stimuli. This article is protected by copyright. All rights reserved. |
