DISC1 as a therapeutic target for mental illnesses

Hikida, Takatoshi; Gamo, Nao J.; Sawa, Akira

doi:10.1517/14728222.2012.719879

Cited by 36 publications

(36 citation statements)

References 113 publications

(138 reference statements)

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“…1–4 To dissect the functional protein domains in the larval neurons, we overexpressed a series of mutant DISC1 proteins (Fig. 1C) and analyzed their localization (Fig.…”

Section: Resultsmentioning

confidence: 99%

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DISC1 causes associative memory and neurodevelopmental defects in fruit flies

et al. 2016

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Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/ mutation constructs have revealed the importance of amino terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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“…1–4 To dissect the functional protein domains in the larval neurons, we overexpressed a series of mutant DISC1 proteins (Fig. 1C) and analyzed their localization (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1–4 In this study, we expressed human DISC1 in developing fruit fly neurons, and performed behavioral and neurodevelopmental studies in living organisms (summarized in Table 1). We have shown that overexpression of DISC1 causes associative memory defects in fruit fly larvae.…”

Section: Discussionmentioning

confidence: 99%

DISC1 causes associative memory and neurodevelopmental defects in fruit flies

et al. 2016

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“…DISC1 was initially identified when a loss-of-function translocation in the gene was discovered in Scottish families who suffered from mental disease (27–31). Subsequently, DISC1 has been implicated in bipolar disorder (32), MDD (33), and autism (34).…”

Section: Discussionmentioning

confidence: 99%

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

El-Hassar¹,

Simen²,

Duque³

et al. 2014

Biological Psychiatry

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Background Disrupted in Schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulate cAMP signaling by increasing PDE4 catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. Methods We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by shRNA viral knockdown or in vitro by dialysis of DISC1 antibodies. Results We found that DISC1 disruption resulted in an increase of: mGluR-induced intracellular Ca2+ waves, SK-mediated hyperpolarization and a decrease of TRPC-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels. Conclusions Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of PFC activity through the loss of cAMP regulation of mGluR-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

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“…These interacting proteins include nuclear distribution protein NudE-like 1 (NDEL1), platelet-activating factor acetylhydrolase 1B subunit alpha (PAFAH1B1, a.k.a. LIS1), Bardet-Biedl syndrome 4 (BBS4), Girdin/KIAA1212, phosphodiesterase 4 (PDE4), Kalirin7, TRAF2- and NCK-interacting kinase (TNIK), and glycogen synthase kinase 3β (GSK3β) (Brandon and Sawa, 2011; Hikida et al, 2012). Recent studies have identified even more interactors of DISC1, such as dopamine D2 receptors (D2R) (Su et al, 2014) and mRNA for inositol-1,4,5-trisphosphate receptor type 1 (ITPR1) (Tsuboi et al, 2015).…”

Section: Disc1 As a Scaffold Protein In Neurodevelopment And Synapticmentioning

confidence: 99%

Utility and validity of DISC1 mouse models in biological psychiatry

et al. 2016

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We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10–15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

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DISC1 as a therapeutic target for mental illnesses

Cited by 36 publications

References 113 publications

DISC1 causes associative memory and neurodevelopmental defects in fruit flies

DISC1 causes associative memory and neurodevelopmental defects in fruit flies

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

Utility and validity of DISC1 mouse models in biological psychiatry

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