PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence.
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.
Departments of Psychiatry and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Akiko
A
Hayashi-Takagi
Yoichi
Y
Araki
Mayumi
M
Nakamura
Benedikt
B
Vollrath
Sergio G
SG
Duron
Zhen
Z
Yan
Haruo
H
Kasai
Richard L
RL
Huganir
David A
DA
Campbell
Akira
A
Sawa
D000375:Aging / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C581573:6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)pyrido(2,3-d)pyrimidin-7(8H)-one; C498794:Disc1 protein, mouse; C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D054462:p21-Activated Kinases
mechanism-oriented drug discovery; synapse protection