Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3ß interaction.

Introduction: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3ß (GSK-3ß). Since ketamine activates GSK-3ß, we examined the impact of ketamine on DISC1 and GSK-3ß expression. Methods: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3ß antagonist, lithium. Cleaved-caspase-3, GSK-3ß and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3ß was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium. Results: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3ß, which implicates increased GSK-3ß activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3ß and axonal length. Conclusion: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.

Astrocyte-mediated regulation of BLAWFS1 neurons alleviates risk-assessment deficits in DISC1-N mice.

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons' NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.

Defined co-cultures of glutamatergic and GABAergic neurons with a mutation in DISC1 reveal aberrant phenotypes in GABAergic neurons.

BACKGROUND: Mutations in the gene DISC1 are associated with increased risk for schizophrenia, bipolar disorder and major depression. The study of mutated DISC1 represents a well-known and comprehensively characterized approach to understand neuropsychiatric disease mechanisms. However, previous studies have mainly used animal models or rather heterogeneous populations of iPSC-derived neurons, generated by undirected differentiation, to study the effects of DISC1 disruption. Since major hypotheses to explain neurodevelopmental, psychiatric disorders rely on altered neuronal connectivity observed in patients, an ideal iPSC-based model requires accurate representation of the structure and complexity of neuronal circuitries. In this study, we made use of an isogenic cell line with a mutation in DISC1 to study neuronal synaptic phenotypes in a culture system comprising a defined ratio of NGN2 and ASCL1/DLX2 (AD2)-transduced neurons, enriched for glutamatergic and GABAergic neurons, respectively, to mimic properties of the cortical microcircuitry. RESULTS: In heterozygous DISC1 mutant neurons, we replicated the expected phenotypes including altered neural progenitor proliferation as well as neurite outgrowth, deregulated DISC1-associated signaling pathways, and reduced synaptic densities in cultures composed of glutamatergic neurons. Cultures comprising a defined ratio of NGN2 and AD2 neurons then revealed considerably increased GABAergic synapse densities, which have not been observed in any iPSC-derived model so far. Increased inhibitory synapse densities could be associated with an increased efficiency of GABAergic differentiation, which we observed in AD2-transduced cultures of mutant neurons. Additionally, we found increased neuronal activity in GABAergic neurons through calcium imaging while the activity pattern of glutamatergic neurons remained unchanged. CONCLUSIONS: In conclusion, our results demonstrate phenotypic differences in a co-culture comprising a defined ratio of DISC1 mutant NGN2 and AD2 neurons, as compared to culture models comprising only one neuronal cell type. Altered synapse numbers and neuronal activity imply that DISC1 impacts the excitatory/inhibitory balance in NGN2/AD2 co-cultures, mainly through increased GABAergic input.

Aggregation of Disrupted in Schizophrenia 1 arises from a central region of the protein.

An emerging approach to studying major mental illness is through proteostasis, with the identification of several proteins that form insoluble aggregates in the brains of patients. One of these is Disrupted in Schizophrenia 1 (DISC1), a neurodevelopmentally-important scaffold protein, and product of a classic schizophrenia risk gene. DISC1 aggregates have been detected in post mortem brain tissue from patients with schizophrenia, bipolar disorder and major depressive disorder, as well as various model systems, although the mechanism by which it aggregates is still unclear. Aggregation of two other proteins implicated in mental illness, TRIOBP-1 and NPAS3, was shown to be dependent on very specific structural regions of the protein. We therefore looked at the domain structure of DISC1, and investigated which structural elements are key for its aggregation. While none of the known structured DISC1 regions (named D, I, S and C respectively) formed aggregates individually when expressed in neuroblastoma cells, the combination of the D and I regions, plus the linker region between them, formed visible aggregates. Further refinement revealed that a region of approximately 30 amino acids between these two regions is critical for aggregation, and deletion of this region is sufficient to abolish the aggregation propensity of DISC1. This finding from mammalian cell culture contrasts with the recent determination that the C-region of DISC1 can aggregate in vitro, although some variations of the C-terminal of DISC1 could aggregate in our system. It therefore appears likely that DISC1 aggregation, implicated in mental illness, can occur through at least two distinct mechanisms.

Gene Polymorphisms and Expression of NRG1, DAOA, and DISC1 Genes in a Chinese Han Population with an Ultra-High Risk for Psychosis.

Purpose: Although there is previous evidence supporting that ultra-high risk (UHR) for psychosis transformation is associated with NRG1, DAOA, and DISC1 genes, there have been no relevant studies in the Chinese population. The objective of the current study was to explore the gene polymorphism and expression of NRG1, DAOA, and DISC1 genes in a Han population with UHR for psychosis in China. Methods: Eighteen UHR individuals, 61 first-degree relatives of patients with schizophrenia (FDR), 55 first-episode psychosis individuals (FEP), and 61 healthy controls (HC) were enrolled in the study. The genotypes at four loci of the NRG1 gene, four loci of the DAOA gene, and two loci of the DISC1 gene were tested for all subjects, and mRNAs of NRG1 and DISC1 were examined and analyzed in a pairwise comparison among the four groups. Statistical analysis of genetics was performed using snpStats software. For the case-control association analysis, a single site association study, epistatic effect analysis, and haplotype analysis were used to explore the association of the above genes. Results: This study found that rs3918341 in the DAOA gene was associated with susceptibility to UHR by single site association analysis. Epistatic effect analysis results showed that the NRG1 gene interacted with the DAOA gene and DISC1 gene in the susceptibility to UHR. Haplotype association analysis showed that all haplotypes were not significantly associated with UHR. NRG1 mRNA was significantly downregulated in the UHR group compared with the HC group as well as the FEP group. Conclusion: Our preliminary results show that NRG1, DAOA, and DISC1 genes may play a role in psychosis onset, opening the way to the identification of prognostic biomarkers.

Disrupted in Schizophrenia 1 Reverse Ectopic Migration of Neural Precursors in Mouse Hilus After Pilocarpine-Induced Status Epilepticus.

Neural precursors in the subgranular zone (SGZ) can be stimulated by status epilepticus (SE) and ectopically migrate to the hilus. These mislocated cells serve as "potential pacemakers" of spontaneous recurrent seizures, and targeting them could potentially reverse the seizure process. Disrupted-in-Schizophrenia 1 (DISC1) regulates hippocampal neurogenesis after seizures both in vitro and in vivo. Our previous study found that DISC1 was colocalized with neural precursors in the hilus after SE. However, its molecular mechanism and pathways contribute to the ectopic migration of neural precursors to the hilus induced by SE awaits exploration. Here, we showed that both Reelin-ApoER2/EphB2 and Reelin-Integrin ß1/Integrin α5 axes may participate in the modulation of neurogenesis after SE. Especially, DISC1, as a protective role, might partly reversed the ectopic progenitor migration via EphB2 pathway. Our findings demonstrated that DISC1 played a protective role in the ectopic migration of neural precursors induced by SE insults and DISC1 could be an attractive new target for the treatment of epilepsy.

DISC1 as a prognostic biomarker correlated with immune infiltrates in gastric cancer.

Multiple mental diseases could arise in people who have the disrupted in schizophrenia 1 (DISC1) gene. However, it was unknown how DISC1 might contribute to the development of tumors and immune responses. We extracted data from the Cancer Genome Atlas (TCGA) and TISIDB databases from stomach adenocarcinoma (STAD) patients, which revealed that DISC1 overexpression was closely associated with tumor histological type (mucinous vs. tubular, OR = 2.860, CI = 1.423-5.872, p = 0.004), as well as tumor stage and grade. Furthermore, the higher the DISC1 expression, the lower the overall 10-year survival rate. Patients with low DISC1 expression had a significantly longer progression-free interval (PFI) and disease-specific survival (DSS) than patients with high DISC1 expression. However, patients with higher DISC1 expression in the T3&T4, N0&N1 and M0 subgroups had poorer prognosis in terms of OS, DSS and PFI, as could be seen in the subgroup survival analysis. Public datasets were used to predict lncRNA-miRNA-DISC1 regulation. DISC1 was significantly up-regulated in GC(gastric cancer), and its expression levels showed a moderate to strong positive correlation with infiltration levels of effector memory T cells (Tem) and central memory T cells (Tcm), and a negative correlation was observed with Th17 cells and NK CD56bright cells. In addition, concomitant with the high expression of the DISC1 gene was a decrease in MHC-I (Major Histocompatibility Complex-I)expression and an increase in MHC-II expression, and altered chemokine expression. The upregulation of CXCL12 and CXCR4 expression could be caused by an increase in DISC1 expression. The above expression variability and correlation suggest a role for DISC1 in regulating tumor immunity in GC. These findings suggest that high expression of DISC1 could be an independent prognostic factor for GC.

50-kHz ultrasonic vocalizations do not signal social anhedonia in transgenic DISC1 rats.

Patients diagnosed with neuropsychiatric disorders, such as autism and schizophrenia, suffer from disorganized speech. The disrupted-in-schizophrenia 1 (DISC1) protein pathway is considered a risk factor for the development of several psychiatric disorders and plays an important role in the dysregulation of dopamine (DA), which in turn plays an important role in the regulation of ultrasonic vocalizations (USVs) in rats. Moreover, the DISC1 protein pathway has been identified as a cause of social anhedonia, that is, a decrease in the drive for social interactions. USVs transmit specific affective information to other rats, with 50-kHz calls indicating a positive affective state in rats. Dysregulation of the dopaminergic system impacts the qualitative and quantitative features of USVs, such as duration, peak frequency, and the call rate. In this study, we thus used a well-established transgenic DISC1 (tgDISC1) rat line to investigate whether the neural (decreased DA levels in the dorsal striatum, amygdala, and hippocampus (HPC)) and behavioral (social anhedonia) features of tgDISC1 rats could be manifested through the modulation of their 50-kHz USVs. Analyses of three features (call rate, duration, and peak frequency) of all 50-kHz revealed no significant differences between groups, suggesting decreased DA levels in the dorsal striatum and amygdala, and HPC may affect social interaction but leave 50-kHz USV production intact.

Effects of representative point mutations on dynamic behavior of the DISC1-Ndel1 complex: a molecular dynamics study.

It has been found that the development of schizophrenia and some other psychiatric disorders is related to defects in the normal functioning of Disrupted-In-Schizophrenia 1 (DISC1). It is a large-sized protein containing 855 residues and acts as an active hub at the core of many interactions with various proteins. On the other hand, NudE Neurodevelopment Protein 1 Like 1 (Ndel1) plays a role in nervous system development via interaction with the DISC1. It was shown that some point mutations on DISC1 have clinical implications. In line with these reports, here we have used the NMR structure of the wild-type (WT) C-terminal tail of DISC1 in complex with the N-terminal fragment of Ndel1, and have constructed the three-dimensional structures of L62Q and L29Q mutants, as the pathologic variants of the complex. The time-dependent interaction of DISC1 with Ndel1 in the WT complex and mutants was simulated by performing molecular dynamics (MD) simulation using programs in the GROMACS package. It was found that the flexibility of residues in some regions of the protein chains increases, and secondary structural changes from ordered toward unordered one leads to destabilizing of the complex in mutants. Destabilization of the complex upon substitution of Leu by Gln was also confirmed by analysis of the contact map plot.Communicated by Ramaswamy H. Sarma.

DISC1 inhibits GSK3ß activity to prevent tau hyperphosphorylation under diabetic encephalopathy.

Diabetic encephalopathy (DE) is a common complication of type 2 diabetes (T2D), especially in those patients with long T2D history. Persistent high glucose (HG) stimulation leads to neuron damage and manifests like Alzheimer's disease's pathological features such as neurofilament tangle. However, the precise mechanism of high-glucose-induced tau hyperphosphorylation is not fully revealed. We here gave evidence that Disrupted in schizophrenia 1 protein (DISC1) could interact with glycogen synthase kinase 3ß (GSK3ß) and inhibit its activity to prevent tau hyperphosphorylation. By using DB/DB mice as animal model and HG-treated N2a cell as cell model, we found that DISC1 was downregulated both in vivo and in vitro, complicated with Tau hyperphosphorylation and GSK3ß activation. Further, we identified DISC1 interacted with GSK3ß by its 198th-237th amino acid residues. Overexpression of full length DISC1 but not mutated DISC1 lacking this domain could prevent HG induced tau hyperphosphorylation. Taken together, our work revealed DISC1 could be an important negative modulators of tau phosphorylation, and suggested that preservation of DISC1 could prevent HG induced neuron damage.

Evidence of DISC1 as an arsenic binding protein and implications regarding its role as a translational activator.

Disrupted-in-schizophrenia-1 (DISC1) is a scaffolding protein that plays a pivotal role in orchestrating signaling pathways involved in neurodevelopment, neural migration, and synaptogenesis. Among those, it has recently been reported that the role of DISC1 in the Akt/mTOR pathway can shift from a global translational repressor to a translational activator in response to oxidative stress induced by arsenic. In this study we provide evidence that DISC1 can directly bind arsenic via a C-terminal cysteine motif (C-X-C-X-C). A series of fluorescence-based binding assays were conducted with a truncated C-terminal domain construct of DISC1 and a series of single, double, and triple cysteine mutants. We found that arsenous acid, a trivalent arsenic derivative, specifically binds to the C-terminal cysteine motif of DISC1 with low micromolar affinity. All three cysteines of the motif are required for high-affinity binding. Electron microscopy experiments combined with in silico structural predictions reveal that the C-terminal of DISC1 forms an elongated tetrameric complex. The cysteine motif is consistently predicted to be located within a loop, fully exposed to solvent, providing a simple molecular framework to explain the high-affinity of DISC1 toward arsenous acid. This study sheds light on a novel functional facet of DISC1 as an arsenic binding protein and highlights its potential role as both a sensor and translational modulator within Akt/mTOR pathway.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.

Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders' pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).

Electroacupuncture improves cognitive impairment in diabetic cognitive dysfunction rats by regulating the mitochondrial autophagy pathway.

BACKGROUND: Diabetes-associated cognitive dysfunction has become a major public health concern. However, the mechanisms driving this disease are elusive. Herein, we explored how electroacupuncture improves learning and memory function in diabetic rats. METHODS: The diabetic model was established by intraperitoneal injection of streptozotocin (STZ) in adult Sprague-Dawley rats. Rats were fed on high-fat and high-sugar diets. Learning and memory functions were assessed using behavioral tests. The hematoxylin and eosin (H&E) staining, Western blotting, real-time PCR, ELISA, immunohistochemistry, and transmission electronic microscopy (TEM) was performed to test related indicators. RESULTS: High-fat and high-sugar diets impaired learning and memory function in rats, while electroacupuncture treatment reversed these changes. The model group presented highly prolonged escape latency compared to the control group, indicating impaired learning and memory functions. The TEM examination showed that electroacupuncture enhanced Aß clearance and mitochondrial autophagy in hippocampal neuronal cells by increasing DISC1 expression. CONCLUSIONS: Electroacupuncture improves learning and memory function in diabetic rats by increasing DISC1 expression to promote mitophagy. This enhanced Aß clearance, alleviating cytotoxicity in hippocampal neuronal cells.

Disrupted-in-schizophrenia-1 is required for normal pyramidal cell-interneuron communication and assembly dynamics in the prefrontal cortex.

We interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations defined as coactivations within 25 ms were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data, thus, reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting INT responsiveness to glutamatergic drive.

Generation of two induced pluripotent stem cell lines (TMOi001-A-5, TMOi001-A-6) carrying variants in DISC1 exon 2 using CRISPR/Cas9 gene editing.

DISC1 is a scaffold protein involved in key developmental processes such as neuronal migration, differentiation and neurogenesis. Genetic variants of the DISC1 gene have been linked to neuropsychiatric disorders like schizophrenia, bipolar disorder and major depression. Here, we generated two isogenic iPSC lines carrying mutations in DISC1 exon 2 using CRISPR/Cas9 gene editing. Both lines express pluripotency markers, can be differentiated into the three germ layers and present a normal karyotype. The generated iPSC lines can be used to study the implications of DISC1 mutations in the context of neuropsychiatric diseases in vitro.

Advantages and Limitations of Animal Schizophrenia Models.

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

Polysialylation in a DISC1 Mutant Mouse.

Schizophrenia is a serious psychiatric disorder that affects the social life of patients. Psychiatric disorders are caused by a complex combination of genetic (G) and environmental (E) factors. Polysialylation represents a unique posttranslational modification of a protein, and such changes in neural cell adhesion molecules (NCAMs) have been reported in postmortem brains from patients with psychiatric disorders. To understand the G × E effect on polysialylated NCAM expression, in this study, we performed precise measurements of polySia and NCAM using a disrupted-in-schizophrenia 1 (DISC1)-mutant mouse (G), a mouse model of schizophrenia, under acute stress conditions (E). This is the first study to reveal a lower number and smaller length of polySia in the suprachiasmatic nucleus of DISC1 mutants relative to those in wild-type (WT) mice. In addition, an analysis of polySia and NCAM responses to acute stress in five brain regions (olfactory bulb, prefrontal cortex, suprachiasmatic nucleus, amygdala, and hippocampus) revealed that the pattern of changes in these responses in WT mice and DISC1 mutants differed by region. These differences could indicate the vulnerability of DISC1 mutants to stress.

Disrupted in Schizophrenia 1 Regulates Ectopic Neurogenesis in the Mouse Hilus After Pilocarpine-induced Status Epilepticus.

Augmentation of neurogenesis and migration of newly born neurons into ectopic regions like the hilus play critical roles during the pathophysiology of acute kindled seizures. Evidence shows that disrupted in schizophrenia 1 (DISC1) has an influence on adult neurogenesis in the dentate gyrus (DG); however, its role of regulating neurogenesis and mispositioned newborn neurons in the hilus after status epilepticus (SE) remains unknown. Using double immunofluorescence staining, the present study clarifies that DISC1 is co-expressed with nearly all of the neuronal markers, which are characterized by different stages of neuronal development, after pilocarpine-induced SE in mice. This reveals that DISC1 takes part in the modulation of neurogenesis in the hilus post-SE. Unexpectedly, an interesting phenomenon was observed as well. Some glial fibrillary acidic protein (GFAP)-positive cells in the hilus appeared to encircle the DISC1-positive cells, which possibly indicated that DISC1 may participate in the process of neuronal or neural development associated with astrocytes such as phagocytosis, dendritic spine development, synaptic transmission, and developmental and synaptic plasticity.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model.

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.