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

摘要: Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies drug for mental disorders are awaited. Schizophrenia is a devastating disorder with synaptic disconnectivity involved its pathophysiology. Reduction the dendritic spine density major alteration that reproducibly reported cerebral cortex patients schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), factor influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, regulatory role postsynaptic association NMDA-type glutamate receptor, Kalirin-7, Rac1. Prolonged knockdown DISC1 leads deterioration, reminiscent pathology Thus, we tested effects novel inhibitors p21-activated kinases (PAKs), targets Rac1, on deterioration elicited by expression DISC1. These not only significantly ameliorated triggered but also partially reversed size deteriorated synapses culture. One these PAK prevented progressive adolescence as shown vivo two-photon imaging behavioral deficit prepulse inhibition adulthood mouse model. The efficacy may have implications related general.