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

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.mechanism-oriented drug discovery | synapse protection

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

“…Many molecular components involved in neurogenesis, cell migration, specific targeting, and specific synapse formation of both excitatory and inhibitory neurons have been identified, some of which have been implicated in schizophrenia (e.g., ERBB4/NRG1, Del Pino et al, 2013; Flames et al, 2004; DISC1, Brandon and Sawa, 2011; some synaptic molecules, Hayashi-Takagi et al, 2014; O’Dushlaine et al, 2011; Pocklington et al, 2014). …”

Synapse pathology and translational applications for schizophrenia

“…Despite the accumulation of evidence supporting synaptic dysregulation in schizophrenia, the success of therapeutic strategies aimed at modulating synaptic transmission has unfortunately been limited. However, in one schizophrenic animal model, the DISC1 knockdown mouse, chemical compounds that normalize disease pathways underlying synaptic disturbances not only significantly ameliorate the synaptic deterioration but also partially reverse a behavioral deficit in prepulse inhibition (Hayashi-Takagi et al, 2014). Revealing the schizophrenia-related alterations in specific disease-pathways by using validated animal models and iPS neurons would contribute significantly to the identification of a novel therapeutic strategy.…”

Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex

“…Using the molecular signatures described here, it will become possible for us to identify pathological chains of events introduced in those animals, which may lead to behavioral alterations, namely cognitive deficits. Once we identify critical biological events that are affected in these mouse models, we could devise therapeutic approaches to correct those biological events, by which we may be able to improve behavioral deficits (e.g., [64-69]).…”