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Severe learning deficits of IRS p53 mutant mice are caused by altered NMDA receptor‐dependent signal transduction
Author(s) -
Bobsin Kristin,
Kreienkamp HansJürgen
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13428
Subject(s) - mutant , nmda receptor , signal transduction , neuroscience , receptor , microbiology and biotechnology , biology , chemistry , genetics , gene
Learning and memory is dependent on postsynaptic architecture and signaling processes in forebrain regions. The insulin receptor substrate protein of 53 kD a ( IRS p53, also known as Baiap2) is a signaling and adapter protein in forebrain excitatory synapses. Mice deficient in IRS p53 display enhanced levels of postsynaptic N ‐methyl‐ D ‐aspartate receptors ( NMDAR s) and long‐term potentiation ( LTP ) associated with severe learning deficits. In humans, reduced IRS p53/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 IRS p53 using behavioral tests including contextual fear conditioning and the puzzle box. We show that a 50% reduction in IRS p53 levels strongly affects the performance in fear‐evoking learning paradigms. This correlates with increased targeting of NMDAR s to the postsynaptic density ( PSD ) in hippocampi of both heterozygous and knock out (ko) mice at the expense of extrasynaptic NMDAR s. As hippocampal NMDAR ‐dependent LTP is enhanced in IRS p53‐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‐dependent signaling in heterozygous and IRS p53‐deficient mice, necessary for the transcriptional dependent phase of LTP . In contrast, activation of the MAPK and Akt kinase pathways required for translation‐dependent phase of LTP are reduced. Our data suggest that loss or even the reduction in IRS p53 increases NMDAR ‐dependent cAMP responsive element‐binding protein activation in the hippocampus, and interferes with the ability of mice to learn upon anxiety‐related stimuli.We show here that a moderate reduction in the postsynaptic protein IRS p53 in mice leads to an increase in postsynaptic NMDA receptors. Both in heterozygous and IRS p53 deficient mice, this is associated with altered postsynaptic signal transduction, and poor performance of mice in fear‐associated learning paradigms, indicating that precise control of postsynaptic NMDA receptor density is essential for memory formation.