Explore the vast range of titles available.

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 thatmay be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.

An emerging area of research into major mental illnesses is to investigate the formation of insoluble aggregates of specific proteins in the brains of patients with these conditions. These studies are normally based on examining insoluble protein in post mortem brain samples, but, for practical reasons, typically consider only one region of the brain per subject. Here, we tested post mortem brain samples from multiple brain regions of various individuals, which included patients with major depressive disorder, schizophrenia and victims of suicide. Samples from patients with Alzheimer’s disease and control individuals were used for comparison. Notably, 20 tissue samples were available from across the brain of one individual who had both schizophrenia and Alzheimer’s disease. Consistently, while insolubility of DISC1 (Disrupted in Schizophrenia 1), CRMP1 (Collapsin Response Mediator Protein 1) and/or TRIOBP-1 (Trio and F-actin Binding Protein, isoform 1) were often present in multiple brain regions, this was not homogenous across the brain. While this study looks at a relatively small number of subjects, and caution must be taken in over-generalising, it is possible that aggregation of these proteins spreads throughout the brain, in a similar manner to the staging seen in neurodegenerative disease. Previous studies may therefore have underestimated the prevalence of protein aggregation in mental illness, due to this heterogeneity of insoluble protein across the brain.

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.

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 β1/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.

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.

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. 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. 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 Aβ clearance and mitochondrial autophagy in hippocampal neuronal cells by increasing DISC1 expression. Electroacupuncture improves learning and memory function in diabetic rats by increasing DISC1 expression to promote mitophagy. This enhanced Aβ clearance, alleviating cytotoxicity in hippocampal neuronal cells.

Encoding a key ‘hub’ scaffolding protein, the ‘Disrupted-In-Schizophrenia-1’ (DISC1) gene has been strongly implicated in brain development and functions. Genetic variance in this gene is associated with major neuropsychiatric disorders, including schizophrenia, bipolar disorder, and major depression. DISC1 is abundantly expressed in the brain of humans and various model organisms. Here, we discuss currently available animal models of DISC1-related brain deficits and their clinical relevance. We focus on evolutionarily conserved (shared) mechanisms and species-specific phenotypes, especially in newly developed zebrafish (Danio rerio) models, to better understand the uniquely complex role of DISC1 in the molecular pathogenesis of neurobehavioral abnormalities relevant to human neuropsychiatric disorders.

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex in great apes and humans, but not other primates. We performed stereological counts of the VENs in FI and LA (limbic anterior, a component of anterior cingulate cortex) in great apes and in humans. The VENs are more numerous in humans than in apes, although one gorilla approached the lower end of the human range. We also examined the ontological development of the VENs in FI and LA in humans. The VENs first appear in small numbers in the 36th week post-conception, are rare at birth, and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than in the left in FI and LA in postnatal brains of apes and humans. This asymmetry in VEN numbers may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, which contains FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. The VENs appear to be projection neurons, although their targets are unknown. We made a preliminary study of the connections of FI cortex based on diffusion tensor imaging in the brain of a gorilla. The VEN-containing regions connect to the frontal pole as well as to other parts of frontal and insular cortex, the septum, and the amygdala. It is likely that the VENs in FI are projecting to some or all of these structures and relaying information related to autonomic control, decision-making, or awareness. The VENs selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing peptide (GRP) which are also expressed in another population of closely related neurons, the fork cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations may be related to the VEN and fork cells and may be involved in the regulation of appetite. The loss of these cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. We found that the protein encoded by the gene DISC1 (disrupted in schizophrenia) is preferentially expressed by the VENs. DISC1 has undergone rapid evolutionary change in the line leading to humans, and since it suppresses dendritic branching it may be involved in the distinctive VEN morphology.

Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D -serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D -serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D -serine production. To elucidate DISC1–SR interactions in vivo , we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D -serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D -serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D -serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D -serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.

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.