Disrupted In Schizophrenia 1 Knockdown Research Articles

DISC1 promotes translation maintenance during sodium arsenite-induced oxidative stress

Variation in Disrupted-in-Schizophrenia 1 (DISC1) increases the risk for neurodegenerative diseases, schizophrenia, and other mental disorders. However, the functions of DISC1 associated with the development of these diseases remain unclear. DISC1 has been reported to inhibit Akt/mTORC1 signaling, a major regulator of translation, and recent studies indicate that DISC1 could exert a direct role in translational regulation. Here, we present evidence of a novel role of DISC1 in the maintenance of protein synthesis during oxidative stress. In order to investigate DISC1 function independently of Akt/mTORC1, we used Tsc2−/− cells, where mTORC1 activation is independent of Akt. DISC1 knockdown enhanced inhibition of protein synthesis in cells treated with sodium arsenite (SA), an oxidative agent used for studying stress granules (SGs) dynamics and translational control. N-acetyl-cysteine inhibited the effect of DISC1, suggesting that DISC1 affects translation in response to oxidative stress. DISC1 decreased SGs number in SA-treated cells, but resided outside SGs and maintained protein synthesis independently of a proper SG nucleation. DISC1-dependent stimulation of translation in SA-treated cells was supported by its interaction with eIF3h, a component of the canonical translation initiation machinery. Consistent with a role in the homeostatic maintenance of translation, DISC1 knockdown or overexpression decreased cell viability after SA exposure. Our data suggest that DISC1 is a relevant component of the cellular response to stress, maintaining certain levels of translation and preserving cell integrity. This novel function of DISC1 might be involved in its association with pathologies affecting tissues frequently exposed to oxidative stress.

Transient Knock-Down of Prefrontal DISC1 in Immune-Challenged Mice Causes Abnormal Long-Range Coupling and Cognitive Dysfunction throughout Development.

Compromised brain development has been hypothesized to account for mental illness. This concept was underpinned by the function of the molecule disrupted-in-schizophrenia 1 (DISC1), which represents an intracellular hub of developmental processes and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show impaired prefrontal–hippocampal function and cognitive abilities throughout development and at adulthood, especially when combined with early environmental stressors, such as maternal immune activation (MIA). However, the contribution of abnormal DISC1-driven maturation of either prefrontal cortex (PFC) or hippocampus (HP) to these deficits is still unknown. Here, we use in utero electroporation to restrict the DISC1 knock-down to prefrontal layer II/III pyramidal neurons during perinatal development and expose these mice to MIA as an environmental stressor (dual-hit GPFCE mice, both sexes). Combining in vivo electrophysiology and neuroanatomy with behavioral testing, we show that GPFCE mice at neonatal age have abnormal patterns of oscillatory activity and firing in PFC, but not HP. Abnormal firing rates in PFC of GPFCE mice relate to sparser dendritic arborization and lower spine density. Moreover, the long-range coupling within prefrontal–hippocampal networks is decreased at this age. The transient prefrontal DISC1 knock-down was sufficient to permanently perturb the prefrontal–hippocampal communication and caused poorer recognition memory performance at pre-juvenile age. Thus, developmental dysfunction of prefrontal circuitry causes long-lasting disturbances related to mental illness.SIGNIFICANCE STATEMENT Hypofrontality is considered a main cause of cognitive deficits in mental disorders, yet the underlying mechanisms are still largely unknown. During development, long before the emergence of disease symptoms, the functional coupling within the prefrontal–hippocampal network, which is the core brain circuit involved in cognitive processing, is reduced. To assess to which extent impaired prefrontal development contributes to the early dysfunction, immune-challenged mice with transient DISC1 knock-down confined to PFC were investigated in their prefrontal–hippocampal communication throughout development by in vivo electrophysiology and behavioral testing. We show that perturbing developmental processes of prefrontal layer II/III pyramidal neurons is sufficient to diminish prefrontal–hippocampal coupling and decrease the cognitive performance throughout development.

DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders

Our knowledge of how genetic risk variants contribute to psychiatric disease is mainly limited to neurons. However, the mechanisms whereby the same genetic risk factors could affect the physiology of glial cells remain poorly understood. We studied the role of a psychiatric genetic risk factor, Disrupted-In-Schizophrenia-1 (DISC1), in metabolic functions of astrocytes. We evaluated the effects of knockdown of mouse endogenous DISC1 (DISC1-KD) and expression of a dominant-negative, C-terminus truncated human DISC1 (DN-DISC1) on the markers of energy metabolism, including glucose uptake and lactate production, in primary astrocytes and in mice with selective expression of DN-DISC1 in astrocytes. We also assessed the effects of lactate treatment on altered affective behaviors and impaired spatial memory in DN-DISC1 mice. Both DISC1-KD and DN-DISC1 comparably decreased mRNA and protein levels of glucose transporter 4 and glucose uptake by primary astrocytes. Decreased glucose uptake was associated with reduced oxidative phosphorylation and glycolysis as well as diminished lactate production in vitro and in vivo. No significant effects of DISC1 manipulations in astrocytes were observed on expression of the subunits of the electron transport chain complexes or mitofilin, a neuronal DISC1 partner. Lactate treatment rescued the abnormal behaviors in DN-DISC1 male and female mice. Our results suggest that DISC1 may be involved in the regulation of lactate production in astrocytes to support neuronal activity and associated behaviors. Abnormal expression of DISC1 in astrocytes and resulting abnormalities in energy supply may be responsible for aspects of mood and cognitive disorders observed in patients with major psychiatric illnesses.

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation.

Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the 'Mitochondrial contact site and Cristae Organizing system' (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network. Moreover, DISC1 depleted cells have decreased mitochondrial DNA (mtDNA) content and steady state levels of oxidative phosphorylation (OXPHOS) subunits. As a consequence, OXPHOS complexes and supercomplexes are partially disassembled in DISC1 knockdown cells, which suffer severe bioenergetic defects, evidenced by impaired oxygen consumption, adenosine triphosphate synthesis and mitochondrial membrane potential. Transfection of recombinant full-length human DISC1 restores MICOS complex assembly and rescues OXPHOS function, meanwhile overexpression of the DISC1 truncated form Δ597-854, known to be pathogenic, fails to rescue the bioenergetic impairment caused by DISC1 knockdown. These results should contribute to reveal DISC1 physiological function and potential pathogenic role in severe mental illnesses.

DISC1 regulates astrogenesis in the embryonic brain via modulation of RAS/MEK/ERK signaling through RASSF7.

Disrupted in schizophrenia 1 (DISC1) is known as a high susceptibility gene for schizophrenia. Recent studies have indicated that schizophrenia might be caused by glia defects and dysfunction. However, there is no direct evidence of a link between the schizophrenia gene DISC1 and gliogenesis defects. Thus, an investigation into the involvement of DISC1 (a ubiquitously expressed brain protein) in astrogenesis during the late stage of mouse embryonic brain development is warranted. Here, we show that suppression of DISC1 expression represses astrogenesis in vitro and in vivo, and that DISC1 overexpression substantially enhances the process. Furthermore, mouse and human DISC1 overexpression rescued the astrogenesis defects caused by DISC1 knockdown. Mechanistically, DISC1 activates the RAS/MEK/ERK signaling pathway via direct association with RASSF7. Also, the pERK complex undergoes nuclear translocation and influences the expression of genes related to astrogenesis. In summary, our results demonstrate that DISC1 regulates astrogenesis by modulating RAS/MEK/ERK signaling via RASSF7 and provide a framework for understanding how DISC1 dysfunction might lead to neuropsychiatric diseases.

Neuregulin-1 Regulates Cortical Inhibitory Neuron Dendrite and Synapse Growth through DISC1.

Cortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth. We found that NRG1 increases inhibitory neuron dendrite complexity and glutamatergic synapse formation onto inhibitory neurons and that this effect is blocked by expression of a dominant negative DISC1 mutant, or DISC1 knockdown. We also discovered that NRG1 treatment increases DISC1 expression and its localization to glutamatergic synapses being made onto cortical inhibitory neurons. Mechanistically, we determined that DISC1 binds ErbB4 within cortical inhibitory neurons. Collectively, these data suggest that a NRG1-ErbB4-DISC1 signalling pathway regulates the development of cortical inhibitory neuron dendrite and synaptic growth. Given that NRG1, ErbB4, and DISC1 are schizophrenia-linked genes, these findings shed light on how independent risk factors may signal in a common developmental pathway that contributes to neural connectivity defects and disease pathogenesis.

DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons

Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state.

DISC1 signaling in cocaine addiction: Towards molecular mechanisms of co-morbidity

Substance abuse and other psychiatric diseases may share molecular pathology. In order to test this hypothesis, we examined the role of Disrupted In Schizophrenia 1 (DISC1), a psychiatric risk factor, in cocaine self-administration (SA). Cocaine SA significantly increased expression of DISC1 in the nucleus accumbens (NAc); while knockdown of DISC1 in NAc significantly increased cocaine SA and decreased phosphorylation of GSK-3β at Ser9 compared to scrambled shRNA. Our study provides the first mechanistic evidence of a critical role of DISC1 in drug-induced behavioral neuroadaptations and sheds more light at the shared molecular pathology of drug abuse and other major psychiatric disorders.

Disrupted-in-Schizophrenia-1 Attenuates Amyloid-β Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of β-Site APP-Cleaving Enzyme 1 Levels.

Disrupted-in-Schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of β-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-β (Aβ) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Aβ40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates Aβ generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD.

Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics.

Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood. Here, we showed that DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1, a subunit of the exocyst complex, interacted with DISC1 and affected its recruitment to inositol-1,4,5-trisphosphate receptor 1 (IP3R1). Notably, knockdown of DISC1 and EXOC1 elicited an exaggerated ER calcium response upon stimulation of IP3R agonists. Similar abnormal ER calcium responses were observed in hippocampal neurons from DISC1-deficient mutant mice. Moreover, perturbation of ER calcium dynamics upon DISC1 knockdown was effectively reversed by treatment with antipsychotic drugs, such as clozapine and haloperidol. These results collectively indicate that DISC1 is a regulatory factor in ER calcium dynamics, linking a perturbed intracellular calcium signaling and schizophrenia pathogenesis.

Disrupted-in-schizophrenia 1 (DISC1) Regulates Dysbindin Function by Enhancing Its Stability

Dysbindin and DISC1 are schizophrenia susceptibility factors playing roles in neuronal development. Here we show that the physical interaction between dysbindin and DISC1 is critical for the stability of dysbindin and for the process of neurite outgrowth. We found that DISC1 forms a complex with dysbindin and increases its stability in association with a reduction in ubiquitylation. Furthermore, knockdown of DISC1 or expression of a deletion mutant, DISC1 lacking amino acid residues 403-504 of DISC1 (DISC1(Δ403-504)), effectively decreased levels of endogenous dysbindin. Finally, the neurite outgrowth defect induced by knockdown of DISC1 was partially reversed by coexpression of dysbindin. Taken together, these results indicate that dysbindin and DISC1 form a physiologically functional complex that is essential for normal neurite outgrowth.

Perspectives on disrupted-inschizophrenia 1 signaling in neurogenesis.

Perspectives on disrupted-inschizophrenia 1 signaling in neurogenesis.

DISC1 knockdown impairs the tangential migration of cortical interneurons by affecting the actin cytoskeleton.

Disrupted-in-Schizophrenia 1 (DISC1) is a risk gene for a spectrum of major mental disorders. It has been shown to regulate radial migration as well as dendritic arborization during neurodevelopment and corticogenesis. In a previous study we demonstrated through in vitro experiments that DISC1 also controls the tangential migration of cortical interneurons originating from the medial ganglionic eminence (MGE). Here we first show that DISC1 is necessary for the proper tangential migration of cortical interneurons in the intact brain. Expression of EGFP under the Lhx6 promotor allowed us to analyze exclusively interneurons transfected in the MGE after in utero electroporation. After 3 days in utero, DISC1 deficient interneurons displayed prolonged leading processes and, compared to control, fewer neurons reached the cortex. Time-lapse video microscopy of cortical feeder-layers revealed a decreased migration velocity due to a reduction of soma translocations. Immunostainings indicated that DISC1 is co-localized with F-actin in the growth cone-like structure of the leading process. DISC1 knockdown reduced F-actin levels whereas the overall actin level was not altered. Moreover, DISC1 knockdown also decreased levels of phosphorylated Girdin, which cross-links F-actin, as well as the Girdin-activator pAkt. In contrast, using time-lapse video microscopy of fluorescence-tagged tubulin and EB3 in fibroblasts, we found no effects on microtubule polymerization when DISC1 was reduced. However, DISC1 affected the acetylation of microtubules in the leading processes of MGE-derived cortical interneurons. Together, our results provide a mechanism how DISC1 might contribute to interneuron migration thereby explaining the reduced number of specific classes of cortical interneurons in some DISC1 mouse models.

TRANSIENT NEUROINFLAMMATION IS A KEY MECHANISM MEDIATING THE NEUROPATHOLOGICAL INTERACTIONS BETWEEN PRENATAL IMMUNE CHALLENGE AND PERIPUBERTAL STRESS

Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1.DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured.We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters.Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

DISC1 (Disrupted-in-Schizophrenia-1) Regulates Differentiation of Oligodendrocytes

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.

Regulation of N-Methyl-D-Aspartate Receptors by Disrupted-in-Schizophrenia-1

Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

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

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.

Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi

Disrupted-in-Schizophrenia 1 ( DISC1) is a promising genetic risk factor for major mental disorders. Many groups repeatedly reported a role for DISC1 in brain development in various strains of mice and rats by using RNA interference (RNAi) approach. Nonetheless, due to the complexity of its molecular disposition, such as many splice variants and a spontaneous deletion in a coding exon of the DISC1 gene in some mouse strains, there have been debates on the interpretation on these published data. Thus, in this study, we address this question by DISC1 knockdown via short-hairpin RNAs (shRNAs) against several distinct target sequences with more than one delivery methodologies into several mouse strains, including C57BL/6, ICR, and 129X1/SvJ. Here, we show that DISC1 knockdown by in utero electroporation of shRNA against exons 2, 6, and 10 consistently results in neuronal migration defects in the developing cerebral cortex, which are successfully rescued by co-expression of full-length DISC1. Furthermore, lentivirus-mediated shRNA also led to migration defects, which is consistent with two other methodologies already published, such as plasmid-mediated and retrovirus-mediated ones. The previous study by Song’s group also reported that, in the adult hippocampus, the phenotype elicited by DISC1 knockdown with shRNA targeting exon 2 was consistently seen in both C57BL/6 and 129S6 mice. Taken together, we propose that some of DISC1 isoforms that are feasible to be knocked down by shRNAs to exon 2, 6, and 10 of the DISC1 gene play a key role for neuronal migration commonly in various mouse strains and rats.

Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits

Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming pathways or "signalosomes." Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and perinatal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.

Disrupted-In-Schizophrenia 1 Regulates Integration of Newly Generated Neurons in the Adult Brain

Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.