PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

Akiko Hayashi-Takagi; Yoichi Araki; Mayumi NakamuraBenedikt VollrathSergio G. DuronZhen YanHaruo KasaiRichard L. HuganirDavid A. CampbellAkira Sawa

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PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

机译：PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

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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. Disruptedin- 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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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第17期|6461-6466|共6页
作者
Akiko Hayashi-Takagi; Yoichi Araki; Mayumi NakamuraBenedikt VollrathSergio G. DuronZhen YanHaruo KasaiRichard L. HuganirDavid A. CampbellAkira Sawa;
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作者单位

Departments of Psychiatry The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

Lab of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, JapanAfraxis, Inc., San Diego, CA 92121Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, NY 14214;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
mechanism-oriented drug discovery; synapse protection;

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

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