ArticleProceedings of the National Academy of Sciences of the United States of America2014
PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 98 citations in OpenAlex.
- Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures.Molecular psychiatry · 2019Pooled it
- From Serendipity to Precision: Integrating AI, Multi-Omics, and Human-Specific Models for Personalized Neuropsychiatric Care.Biomedicines · 2025Review
- FMR1 genetically interacts with DISC1 to regulate glutamatergic synaptogenesis.Schizophrenia (Heidelberg, Germany) · 2024Article
- The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials.International journal of molecular sciences · 2024Review
- PAK inhibitor FRAX486 decreases the metastatic potential of triple-negative breast cancer cells by blocking autophagy.British journal of cancer · 2024Article
- Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction.Frontiers in molecular neuroscience · 2024Article
- Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function.iScience · 2023Article
- Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.Genome medicine · 2023Article
- Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.Science advances · 2023Article
- Animal Models of Relevance to the Schizophrenia Prodrome.Biological psychiatry global open science · 2023Review
- The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype.Frontiers in neuroscience · 2023Review
- Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.CNS neuroscience & therapeutics · 2022Article
- Inka2, a novel Pak4 inhibitor, regulates actin dynamics in neuronal development.PLoS genetics · 2022Article
- Neuroligin-3 and neuroligin-4X form nanoscopic clusters and regulate growth cone organization and size.Human molecular genetics · 2022Article
- The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders.Protein & cell · 2022Review
- Semaphorin3F Drives Dendritic Spine Pruning Through Rho-GTPase Signaling.Molecular neurobiology · 2021Article
- The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex.Molecular psychiatry · 2021Review
- Spine dynamics in the brain, mental disorders and artificial neural networks.Nature reviews. Neuroscience · 2021Review
- CDK4/6 inhibition synergizes with inhibition of P21-Activated Kinases (PAKs) in lung cancer cell lines.PloS one · 2021Article
- Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex.Nature communications · 2020Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.