Understanding the Role of DISC1 in Psychiatric Disease and during Normal Development

Brandon, Nicholas J.; Millar, J. Kirsty; Korth, Carsten; Sive, Hazel; Singh, Karun K.; Sawa, Akira

doi:10.1523/jneurosci.3355-09.2009

Cited by 172 publications

(145 citation statements)

References 52 publications

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“…It is interesting to note that while stabilized b-catenin expression can compensate for the effect of Aspm knockdown on deficits in neurogenesis at this stage, no such compensation is observed in terms of neuronal migration. This is consistent with previous observations that knockdown of positive regulators of Wnt signaling impinges on both neurogenesis and neuronal migration, but that only deficits in neurogenesis can be rescued via increased Wntmediated activity (Brandon et al 2009;Mao et al 2009). …”

Section: Expression Of Stabilized B-catenin Rescues Defects In Wnt Sisupporting

confidence: 93%

ASPM regulates Wnt signaling pathway activity in the developing brain

Buchman¹,

Durak²,

Tsai³

2011

Genes Dev.

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Autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder in which patients display significantly reduced brain size. Mutations in Abnormal Spindle Microcephaly (ASPM) are the most common cause of MCPH. Here, we investigate the underlying functions of Aspm in brain development and find that Aspm expression is critical for proper neurogenesis and neuronal migration. The Wnt signaling pathway is known for its roles in embryogenesis, and genome-wide siRNA screens indicate that ASPM is a positive regulator of Wnt signaling. We demonstrate that knockdown of Aspm results in decreased Wnt-mediated transcription, and that expression of stabilized b-catenin can rescue this deficit. Finally, coexpression of stabilized b-catenin can rescue defects observed upon in vivo knockdown of Aspm. Our findings provide an impetus to further explore Aspm's role in facilitating Wnt-mediated neurogenesis programs, which may contribute to psychiatric illness etiology when perturbed.

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Section: Expression Of Stabilized B-catenin Rescues Defects In Wnt Sisupporting

confidence: 93%

ASPM regulates Wnt signaling pathway activity in the developing brain

Buchman¹,

Durak²,

Tsai³

2011

Genes Dev.

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“…The molecular interactions of both DISC1 and 14-3-3ε are numerous, yet both proteins have been reproducibly implicated in the processes regulating neurite outgrowth and spine density (26,31,33,36,37). 14-3-3ε binds phosphorylated NDEL1 and serves as a positive regulator of NDEL1 function (37), and active NDEL1 is required for neurite outgrowth (38).…”

Section: Discussionmentioning

confidence: 99%

“…DISC1 is a scaffolding protein that is thought to coordinate other synaptic proteins (30)(31)(32), and indeed plays a key role in synaptic spine maintenance in association with the activation of NMDA receptors (33). Thus, we hypothesized that the results from the unbiased approach might reflect a possible defect of a molecular pathway involving DISC1 in the synapse.…”

Section: Nmda Receptor Deficient Mice Show An Age-dependent Deficit Inmentioning

confidence: 99%

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Ramsey

Milenkovic

Oliveira

et al. 2011

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

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NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an agedependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapsespecific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia-1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.glutamate | neurodevelopmental A defining feature of neurons is their ability to alter the number and strength of synaptic connections with experience. At the cellular level, changes in synapse number, or postsynaptic spine density, occur with learning and memory formation (1) or exposure to psychoactive drugs (2), and in neurodevelopmental diseases including schizophrenia (3, 4), fragile-X mental retardation (5), and Rett syndrome (6). At the molecular level, NMDA-type glutamate receptors have long been appreciated for their role in the formation and maintenance of glutamatergic synapses (7), and as mediators of synaptic plasticity (8). Several studies have shown a positive correlation between NMDA receptor activity and spine density (9-12), with notable exceptions (13,14). However, the molecular mechanisms by which NMDA receptors regulate spine density remain to be fully elucidated. In the case of disease states such as schizophrenia, a fuller understanding of this molecular machinery may point to new therapeutic strategies.The striatum represents an ideal brain region in which to further explore the biochemical mechanisms by which NMDA receptors regulate spine density, because the vast majority of neurons (95%) within this brain structure are medium spiny neurons (MSNs), which have densely spinous dendrites, upon which glutamate and dopamine afferents converge (15,16). This neuronal homogeneity allows for ex vivo biochemical preparation of synaptic proteins from a nearly homogenous neuronal substrate. MSNs are thought to be a principal site of action of antipsychotic drugs because they express the highest levels of D2 dopamine receptors (17). Furthermore, they participate in many of the cognitive and limbic behaviors that are altered in schizophrenia (17, 18).We hypothesized that reduced NMDA receptor funct...

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“…The biological functions attributed to the DISC1 protein are complex and highly diverse. For example, previous work suggested that DISC1 plays an important role during neuronal proliferation, differentiation, neurite outgrowth, synapse formation, as well as in the genesis and integration of new neurons in the adult hippocampus (for review, see Brandon et al, 2009). There are also several studies that report that DISC1 is a necessary component for the correct positioning of radially migrating cortical pyramidal neurons (Kamiya et al, 2005;YoungPearse et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1 (DISC1) Is Necessary for the Correct Migration of Cortical Interneurons

Steinecke

Gampe²,

Valkova³

et al. 2012

J. Neurosci.

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Disrupted-in-Schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.

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Understanding the Role of DISC1 in Psychiatric Disease and during Normal Development

Cited by 172 publications

References 52 publications

ASPM regulates Wnt signaling pathway activity in the developing brain

ASPM regulates Wnt signaling pathway activity in the developing brain

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Disrupted-in-Schizophrenia 1 (DISC1) Is Necessary for the Correct Migration of Cortical Interneurons

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