Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1

Hayashi‐Takagi, Akiko; Takaki, Manabu; Graziane, Nicholas; Seshadri, Saurav; Murdoch, Hannah; Dunlop, Allan J.; Makino, Yuichi; Seshadri, Anupamaa; Ishizuka, Koko; Srivastava, Deepak P.; Xie, Zhong; Baraban, Jay M.; Houslay, Miles D.; Tomoda, Toshifumi; Brandon, Nicholas J.; Kamiya, Atsushi; Yan, Zhen; Penzes, Peter; Sawa, Akira

doi:10.1038/nn.2487

Cited by 373 publications

(470 citation statements)

References 50 publications

Supporting

Mentioning

443

Contrasting

Order By: Relevance

“…Because DISC1 is involved in essentially all aspects of neurodevelopment (4-7, 11), and because more than a dozen cytosolic proteins are reported to interact with DISC1 (6, 8,[28][29][30], it is likely that DISC1 acts as a scaffold protein inside neurons, recruiting various signaling components to exert its specific function at different developmental stages. It is therefore not surprising that, in contrast to our results, DISC1 has recently been reported to interact with another RAC1-GEF, Kalirin-7, and to inhibit the RAC1 signaling during dendritic spine morphogenesis (31). Despite the differences, these studies together suggest that mutations of genes involved in the RAC-PAK signaling pathway might cause schizophrenia or other related mental illnesses.…”

Section: Discussioncontrasting

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

show abstract

Section: Discussioncontrasting

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Kal-7/Rac1 cascade and Rac-1 activation in response to NMDA receptor activation in both neuronal cultures and rat brain in vivo 196 are important for the activitydependent spine morphology and functional plasticity 197 . In addition to schizophrenia, genetic association and rare variants in DISC1 have been associated with autism and Asperger's syndrome 198 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

“…Several groups have reproducibly reported that DISC1 is expressed in the glutamatergic postsynapses (10)(11)(12). In primary neuron culture, prolonged DISC1 knockdown results in the synaptic deterioration (decrease in spine density and size) after transient outgrowth in the pathological course (10).…”

mentioning

confidence: 96%

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

Hayashi‐Takagi

Araki

Nakamura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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

show abstract

Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1

Cited by 373 publications

References 50 publications

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Dendritic spine actin cytoskeleton in autism spectrum disorder

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

Contact Info

Product

Resources

About