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

Akiko Hayashi-Takagi, Yoichi Araki, Mayumi Nakamura, Benedikt Vollrath, Sergio G. Duron, Zhen Yan, Haruo Kasai, Richard L. Huganir, David A. Campbell, Akira Sawa

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish (US)
Pages (from-to)6461-6466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number17
DOIs
StatePublished - Apr 29 2014

Keywords

  • Mechanism-oriented drug discovery
  • Synapse protection

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence'. Together they form a unique fingerprint.

Cite this