| 1 | J. Neurochem. 2015 Nov -1: -1 |
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| PMID | 26560964 |
| Title | Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor dependent signal transduction. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia |
| 2 | Nat. Neurosci. 2015 Mar 18: 435-43 |
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| PMID | 25622145 |
| Title | Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. |
| Abstract | Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects. |
| SCZ Keywords | schizophrenia |
| 3 | Neuropharmacology 2016 Jan 100: 27-39 |
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| PMID | 26275848 |
| Title | IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders. |
| Abstract | IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. |
| SCZ Keywords | schizophrenia |