Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 53 kDa insulin receptor substrate protein (IRSp53) is highly enriched in the brain. Despite evidence that links mutations of IRSp53 with autism and other neuropsychiatric problems, the functional significance of this protein remains unclear. We used light and electron microscopic immunohistochemistry to demonstrate that IRSp53 is expressed throughout the adult rat brain. Labeling concentrated selectively in dendritic spines, where it was associated with the postsynaptic density (PSD). Surprisingly, its organization within the PSD of spiny excitatory neurons of neocortex and hippocampus differed from that within spiny inhibitory neurons of neostriatum and cerebellar cortex. The present data support previous suggestions that IRSp53 is involved in postsynaptic signaling, while hinting that its signaling role may differ in different types of neurons.
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PMID:Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons. 2463 75

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.
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PMID:Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. 2562 45

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'.
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PMID:IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders. 2627 48

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 behavioral 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-dependent signaling in heterozygous and IRSp53-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 IRSp53 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 IRSp53 in mice leads to an increase in postsynaptic NMDA receptors. Both in heterozygous and IRSp53 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.
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PMID:Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor-dependent signal transduction. 2656 Sep 64

Genetic defects in SHANK genes are associated with autism. Deletions and truncating mutations suggest haploinsufficiency for Shank3 as a major cause of disease which may be analyzed in appropriate Shank deficient mouse models. Here we will focus on the functional analysis of missense mutations found in SHANK genes. The relevance of most of these mutations for Shank function, and their role in autism pathogenesis is unclear. This is partly due to the fact that mutations spare the most well studied functional domains of Shank3, such as the PDZ and SAM domains, or the short proline-rich motifs which are required for interactions with postsynaptic partners Homer, Cortactin, dynamin, IRSp53 and Abi-1. One set of mutations affects the N-terminal part, including the highly conserved SPN domain and ankyrin repeats. Functional analysis from several groups has indicated that these mutations (e.g., R12C; L68P; R300C, and Q321R) interfere with the critical role of Shank3 for synapse formation. More recently the structural analysis of the SPN-ARR module has begun to shed light on the molecular consequences of mutations in the SPN of Shank3. The SPN was identified as a Ras association domain, with high affinities for GTP-bound, active forms of Ras and Rap. The two autism related mutations in this part of the protein, R12C and L68P, both abolish Ras binding. Further work is directed at identifying the consequences of Ras binding to Shank proteins at postsynaptic sites.
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PMID:Functional Relevance of Missense Mutations Affecting the N-Terminal Part of Shank3 Found in Autistic Patients. 3013 75

IRSp53 (also known as BAIAP2) is an abundant excitatory postsynaptic scaffolding protein implicated in autism spectrum disorders (ASD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD). IRSp53 is expressed in different cell types across different brain regions, although it remains unclear how IRSp53 deletion in different cell types affects brain functions and behaviors in mice. Here, we deleted IRSp53 in excitatory and inhibitory neurons in mice and compared resulting phenotypes in males and females. IRSp53 deletion in excitatory neurons driven by Emx1 leads to strong social deficits and hyperactivity without affecting anxiety-like behavior, whereas IRSp53 deletion in inhibitory neurons driven by Viaat has minimal impacts on these behaviors in male mice. In female mice, excitatory neuronal IRSp53 deletion induces hyperactivity but moderate social deficits. Excitatory neuronal IRSp53 deletion in male mice induces an increased ratio of evoked excitatory and inhibitory synaptic transmission (E/I ratio) in layer V pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), whereas the same mutation does not alter the E/I ratio in female neurons. These results suggest that IRSp53 deletion in excitatory and inhibitory neurons and in male and female mice has distinct impacts on behaviors and synaptic transmission.
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PMID:IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes. 3211 66

Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice.
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PMID:Hyperactive ACC-MDT Pathway Suppresses Prepulse Inhibition in Mice. 3262 12