Neuropathology Of Schizophrenia Research Articles

Multivariate sharp-wave ripples in schizophrenia during awake state.

Schizophrenia (SZ) is a brain disorder characterized by psychotic symptoms and cognitive dysfunction. Recently, irregularities in sharp-wave ripples (SPW-Rs) have been reported in SZ. As SPW-Rs play a critical role in memory, their irregularities can cause psychotic symptoms and cognitive dysfunction in patients with SZ. In this study, we investigated the SPW-Rs in human SZ. We measured whole-brain activity using magnetoencephalography (MEG) in patients with SZ (n = 20) and sex- and age-matched healthy participants (n = 20) during open-eye rest. We identified SPW-Rs and analyzed their occurrence and time-frequency traits. Furthermore, we developed a novel multivariate analysis method, termed "ripple-gedMEG" to extract the global features of SPW-Rs. We also examined the association between SPW-Rs and brain state transitions. The outcomes of these analyses were modeled to predict the positive and negative syndrome scale (PANSS) scores of SZ. We found that SPW-Rs in the SZ (1) occurred more frequently, (2) the delay of the coupling phase (3) appeared in different brain areas, (4) consisted of a less organized spatiotemporal pattern, and (5) were less involved in brain state transitions. Finally, some of the neural features associated with the SPW-Rs were found to be PANSS-positive, a pathological indicator of SZ. These results suggest that widespread but disorganized SPW-Rs underlies the symptoms of SZ. We identified irregularities in SPW-Rs in SZ and confirmed that their alternations were strongly associated with SZ neuropathology. These results suggest a new direction for human SZ research.

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation

A subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation (n = 13) and high inflammation (n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway ‘Hepatic Fibrosis/Hepatic Stellate-Cell Activation’. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix’s regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche.

Cascadic failure and preferential decay via pruning mediated percolation on interdependent networks: implications for schizophrenia

IntroductionDuring adolescence the brain is dynamically changing. Destabilization and acceleration of the normal adolescent synaptic pruning process is likely a contributing factor to the neuropathology of schizophrenia. Details on whether normal pruning effects weaker synapses more or uniformly all synapses with different strengths, needs to be further evaluated. Widespread impairment in structural connectivity in schizophrenic patients involving several cortical and subcortical areas, has been previously described. In this computational study, we investigated a stochastic percolation process in interdependent networks, motivated by pathological synaptic pruning. We examined preferential decay in the connectivity decremental process, as well as differential pruning in interconnected subnetworks. Finally, the speed of the percolation process, as well as the potential for pharmacological interventions of percolation in random networks was explored. Statistical structural properties of decaying networks pinpointed several network attributes which the disintegration and phase transitions qualitatively depended on.ObjectivesThe following objectives were explored: 1.) Apart from a random percolation process, we investigated preferential decay of the connections. We introduced different percolation rules for various connection types. 2.) Based on previous experimental results, we assumed that different interconnected neural subpopulations prune differently, therefore we explored differential pruning process in the subnetworks. 3.) The speed of the percolation was studied and the pharmacological synaptic connectivity change was also analyzed.MethodsWe considered two inter-connected randomly connected networks, where the connections were removed during the percolation process. Simulations were partially performed using Octave on a Lenovo Thinkpad running the Linux operating system and partially performed on a supercomputer at UPPMAX (NAISS Small Compute 2023 Dnr: NAISS 2023/22-102).ResultsWe found that the coupled network system shows rich percolation behaviors with phase transitions for various coupling strength and coupling patterns. The phase transitions of both layers are altered qualitatively between discontinuous, mixed and continuous. Recursively developing percolation in interdependent networks can cause complete fragmentation of these networks, resulting in cascadic failure which might be related to schizophrenia symptoms.Conclusions This computational study analyzes the pruning-mediated percolation in interdependent neural networks. Consequences of the pathological overpruning were related to the attributes of the interdependent network properties. Implications for schizophrenia development and predictions for compensatorial iatrogenic percolation was also pinpointed and discussed.Disclosure of InterestNone Declared

Relationships among the gut microbiome, brain networks, and symptom severity in schizophrenia patients: A mediation analysis

The microbiome-gut-brain axis (MGBA) plays a critical role in schizophrenia (SZ). However, the underlying mechanisms of the interactions among the gut microbiome, brain networks, and symptom severity in SZ patients remain largely unknown. Fecal samples, structural and functional magnetic resonance imaging (MRI) data, and Positive and Negative Syndrome Scale (PANSS) scores were collected from 38 SZ patients and 38 normal controls, respectively. The data of 16S rRNA gene sequencing were used to analyze the abundance of gut microbiome and the analysis of human brain networks was applied to compute the nodal properties of 90 brain regions. A total of 1,691,280 mediation models were constructed based on 261 gut bacterial, 810 nodal properties, and 4 PANSS scores in SZ patients. A strong correlation between the gut microbiome and brain networks (r = 0.89, false discovery rate (FDR) -corrected p < 0.05) was identified. Importantly, the PANSS scores were linearly correlated with both the gut microbiome (r = 0.5, FDR-corrected p < 0.05) and brain networks (r = 0.59, FDR-corrected p < 0.05). The abundance of genus Sellimonas significantly affected the PANSS negative scores of SZ patients via the betweenness centrality of white matter networks in the inferior frontal gyrus and amygdala. Moreover, 19 significant mediation models demonstrated that the nodal properties of 7 brain regions, predominately from the systems of visual, language, and control of action, showed significant mediating effects on the PANSS scores with the gut microbiome as mediators. Together, our findings indicated the tripartite relationships among the gut microbiome, brain networks, and PANSS scores and suggested their potential role in the neuropathology of SZ.

The Relevance of Animal Models of Social Isolation and Social Motivation for Understanding Schizophrenia: Review and Future Directions.

Social dysfunction in schizophrenia includes symptoms of withdrawal and deficits in social skills, social cognition, and social motivation. Based on the course of illness, with social withdrawal occurring prior to psychosis onset, it is likely that the severity of social withdrawal/isolation contributes to schizophrenia neuropathology. We review the current literature on social isolation in rodent models and provide a conceptual framework for its relationship to social withdrawal and neural circuit dysfunction in schizophrenia. We next review preclinical tasks of social behavior used in schizophrenia-relevant models and discuss strengths and limitations of existing approaches. Lastly, we consider new effort-based tasks of social motivation and their potential for translational studies in schizophrenia. Social isolation rearing in rats produces profound differences in behavior, pharmacologic sensitivity, and neurochemistry compared to socially reared rats. Rodent models relevant to schizophrenia exhibit deficits in social behavior as measured by social interaction and social preference tests. Newer tasks of effort-based social motivation are being developed in rodents to better model social motivation deficits in neuropsychiatric disorders. While experimenter-imposed social isolation provides a viable experimental model for understanding some biological mechanisms linking social dysfunction to clinical and neural pathology in schizophrenia, it bypasses critical antecedents to social isolation in schizophrenia, notably deficits in social reward and social motivation. Recent efforts at modeling social motivation using effort-based tasks in rodents have the potential to quantify these antecedents, identify models (eg, developmental, genetic) that produce deficits, and advance pharmacological treatments for social motivation.

Structure-function coupling in white matter uncovers the abnormal brain connectivity in Schizophrenia

Schizophrenia is characterized by dysconnectivity syndrome. Evidence of widespread impairment of structural and functional integration has been demonstrated in schizophrenia. Although white matter (WM) microstructural abnormalities have been commonly reported in schizophrenia, the dysfunction of WM as well as the relationship between structure and function in WM remains uncertain. In this study, we proposed a novel structure-function coupling measurement to reflect neuronal information transfer, which combined spatial-temporal correlations of functional signals with diffusion tensor orientations in the WM circuit from functional and diffusion magnetic resonance images (MRI). By analyzing MRI data from 75 individuals with schizophrenia (SZ) and 89 healthy volunteers (HV), the associations between structure and function in WM regions in schizophrenia were examined. Randomized validation of the measurement was performed in the HV group to confirm the capacity of the neural signal transferring along the WM tracts, referring to quantifying the association between structure and function. Compared to HV, SZ showed a widespread decrease in the structure-function coupling within WM regions, involving the corticospinal tract and the superior longitudinal fasciculus. Additionally, the structure-function coupling in the WM tracts was found to be significantly correlated with psychotic symptoms and illness duration in schizophrenia, suggesting that abnormal signal transfer of neuronal fiber pathways could be a potential mechanism of the neuropathology of schizophrenia. This work supports the dysconnectivity hypothesis of schizophrenia from the aspect of circuit function, and highlights the critical role of WM networks in the pathophysiology of schizophrenia.

Possible Neuropathological Mechanisms Underlying the Increased Complexity of Brain Electrical Activity in Schizophrenia: A Computational Study.

Objective: Schizophrenia is a complex neurodevelopmental illness that is associated with different deficits in the cerebral cortex and neural networks, resulting in irregularity of brain waves. Various neuropathological hypotheses have been proposed for this irregularity that we intend to examine in this computational study. Method : We used a mathematical model of a neuronal population based on cellular automata to examine two hypotheses about the neuropathology of schizophrenia: first, reducing neuronal stimulation thresholds to increase neuronal excitability; and second, increasing the percentage of excitatory neurons and decreasing the percentage of inhibitory neurons to increase the excitation to inhibition ratio in the neuronal population. Then, we compare the complexity of the output signals produced by the model in both cases with real healthy resting-state electroencephalogram (EEG) signals using the Lempel-Ziv complexity measure and see if these changes alter (increase or decrease) the complexity of the neuronal population dynamics. Results: By lowering the neuronal stimulation threshold (i.e., the first hypothesis), no significant change in the pattern and amplitude of the network complexity was observed, and the model complexity was very similar to the complexity of real EEG signals (P > 0.05). However, increasing the excitation to inhibition ratio (i.e., the second hypothesis) led to significant changes in the complexity pattern of the designed network (P < 0.05). More interestingly, in this case, the complexity of the output signals of the model increased significantly compared to real healthy EEGs (P = 0.002) and the model output of the unchanged condition (P = 0.028) and the first hypothesis (P = 0.001). Conclusion: Our computational model suggests that imbalances in the excitation to inhibition ratio in the neural network are probably the source of abnormal neuronal firing patterns and thus the cause of increased complexity of brain electrical activity in schizophrenia.

Increased prefrontal cortical cells positive for macrophage/microglial marker CD163 along blood vessels characterizes a neuropathology of neuroinflammatory schizophrenia

Transcript levels of cytokines and SERPINA3 have been used to define a substantial subset (40%) of individuals with schizophrenia with elevated inflammation and worse neuropathology in the dorsolateral prefrontal cortex (DLPFC). In this study, we tested if inflammatory proteins are likewise related to high and low inflammatory states in the human DLFPC in people with schizophrenia and controls. Levels of inflammatory cytokines (IL6, IL1β, IL18, IL8) and a macrophage marker (CD163 protein) were measured in brains obtained from the National Institute of Mental Health (NIMH) (N = 92). First, we tested for diagnostic differences in protein levels overall, then we determined the percentage of individuals that could be defined as “high” inflammation using protein levels. IL-18 was the only cytokine to show increased expression in schizophrenia compared to controls overall. Interestingly, two-step recursive clustering analysis showed that IL6, IL18, and CD163 protein levels could be used as predictors of “high and low” inflammatory subgroups. By this model, a significantly greater proportion of schizophrenia cases (18/32; 56.25%; SCZ) were identified as belonging to the high inflammatory (HI) subgroup compared to control cases (18/60; 30%; CTRL) [χ2(1) = 6.038, p = 0.014]. When comparing across inflammatory subgroups, IL6, IL1β, IL18, IL8, and CD163 protein levels were elevated in both SCZ-HI and CTRL-HI compared to both low inflammatory subgroups (all p < 0.05). Surprisingly, TNFα levels were significantly decreased (–32.2%) in schizophrenia compared to controls (p < 0.001), and were most diminished in the SCZ-HI subgroup compared to both CTRL-LI and CTRL-HI subgroups (p < 0.05). Next, we asked if the anatomical distribution and density of CD163+ macrophages differed in those with schizophrenia and high inflammation status. Macrophages were localized to perivascular sites and found surrounding small, medium and large blood vessels in both gray matter and white matter, with macrophage density highest at the pial surface in all schizophrenia cases examined. A higher density of CD163+ macrophages, that were also larger and more darkly stained, was found in the SCZ-HI subgroup (+154% p < 0.05). We also confirmed the rare existence of parenchymal CD163+ macrophages in both high inflammation subgroups (schizophrenia and controls). Brain CD163+ cell density around blood vessels positively correlated with CD163 protein levels. In conclusion, we find a link between elevated interleukin cytokine protein levels, decreased TNFα protein levels, and elevated CD163+ macrophage densities especially along small blood vessels in those with neuroinflammatory schizophrenia.

Altered Functional Connectivity Strength in Distinct Brain Networks of Children With Early-Onset Schizophrenia.

Schizophrenia is regarded as a brain network or connectome disorder that is associated with neurodevelopment. Children with early-onset schizophrenia (EOS) provide an opportunity to evaluate the neuropathology of schizophrenia at a very early stage without potential confounding factors. But dysfunction in brain networks of schizophrenia is inconsistent. To identify abnormal functional connectivity (FC) in EOS patients and relationships with clinical symptoms, we aimed to reveal neuroimaging phenotypes of EOS. Prospective, cross-sectional. Twenty-six female/22 male patients (age:14.3 ± 3.45 years) with first-episode EOS, 27 female/22 male age- and gender-matched healthy controls (HC) (age:14.1 ± 4.32). 3-T, resting-state (rs) gradient-echo echo-planar imaging and three-dimensional magnetization-prepared rapid gradient-echo imaging. Intelligence quotient (IQ) was measured by the Wechsler Intelligence Scale-Fourth edition for Children (WISC-IV). The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). FC strength (FCS) from rs functional MRI (rsfMRI) was used to investigate functional integrity of global brain regions. In addition, associations between regionally altered FCS and clinical symptoms in EOS patients were examined. Two-sample t-test controlling for sample size, diagnostic method, brain volume algorithm, and age of the subjects, Bonferroni correction, Pearson's correlation analysis. A P-value <0.05 with a minimum cluster size of 50 voxels was considered statistically significant. Compared with HC, EOS patients had significantly lower total IQ scores (IQ:91.5 ± 16.1), increased FCS in the bilateral precuneus, left dorsolateral prefrontal cortex, left thalamus, and left parahippocampus (paraHIP), and decreased FCS in the right cerebellum posterior lobe and right superior temporal gyrus. The PANSS total score of EOS patients (PANSS total score:74.30 ± 7.23) was found to be positively correlated to FCS in the left paraHIP (r=0.45). Our study revealed that disrupted FC of brain hubs illustrate multiple abnormalities in brain networks in EOS patients. 1 TECHNICAL EFFICACY STAGE: 2.

Investigating brain aging trajectory deviations in different brain regions of individuals with schizophrenia using multimodal magnetic resonance imaging and brain-age prediction: a multicenter study

Although many studies on brain-age prediction in patients with schizophrenia have been reported recently, none has predicted brain age based on different neuroimaging modalities and different brain regions in these patients. Here, we constructed brain-age prediction models with multimodal MRI and examined the deviations of aging trajectories in different brain regions of participants with schizophrenia recruited from multiple centers. The data of 230 healthy controls (HCs) were used for model training. Next, we investigated the differences in brain age gaps between participants with schizophrenia and HCs from two independent cohorts. A Gaussian process regression algorithm with fivefold cross-validation was used to train 90, 90, and 48 models for gray matter (GM), functional connectivity (FC), and fractional anisotropy (FA) maps in the training dataset, respectively. The brain age gaps in different brain regions for all participants were calculated, and the differences in brain age gaps between the two groups were examined. Our results showed that most GM regions in participants with schizophrenia in both cohorts exhibited accelerated aging, particularly in the frontal lobe, temporal lobe, and insula. The parts of the white matter tracts, including the cerebrum and cerebellum, indicated deviations in aging trajectories in participants with schizophrenia. However, no accelerated brain aging was noted in the FC maps. The accelerated aging in 22 GM regions and 10 white matter tracts in schizophrenia potentially exacerbates with disease progression. In individuals with schizophrenia, different brain regions demonstrate dynamic deviations of brain aging trajectories. Our findings provided more insights into schizophrenia neuropathology.

The Influence of Traumatic Memories in Schizophrenia

Since studying psychiatric disorders, Clinicians have observed and reported the abnormal nature of the presence of traumatic memories and the main symptoms they cause in PTSD, an essential aspect of which is memory encoding. The leading cause of traumatic memory flashbacks is the inability to store certain representations of the traumatic event in the hippocampus due to deficits in the hippocampus. Hippocampal deficits are also found in schizophrenia, and some studies suggest that the hippocampus is the central core of the neuropathology of schizophrenia. In contrast, sleep spindles play a vital role in sensory processing and long-term memory consolidation. Studies collected in the field of PTSD suggest that sleep spindles can alleviate mood. However, schizophrenia patients commonly have sleep disturbances and significantly reduce spindles and sleep-dependent memory consolidation. So, in conclusion, it can be speculated that mood swings cause memory encoding problems that the sleep spindles waves cannot handle.

Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System.

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune-inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors.

Review of Experimental Models of Schizophrenia

Schizophrenia is a severe psychiatric disease that has a lifetime prevalence of 1% in most of the populations studied. The neuropathology and psychopathology of Schizophrenia are still poorly understood. This is attributed to the paucity of adequate animal models. Schizophrenia is a disorder of the human brain. Consequently, the potency of animal models in Schizophrenia research is limited to certain aspects of the disease. One of the most difficult aspects of modelling Schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. This review discussed drug-induced animal models of Schizophrenia such as Ketamine (NMDA receptor antagonist), Phencyclidine (NMDA receptor antagonist) etc. It also discussed genetic animal models of Schizophrenia which include but not limited to Schizophrenia susceptibility Genes, Neuregulin-1(NRG1), DAT gene, Zinc finger DHH-type3 containing 8 (ZDHHC8) and Dysbindin. It went further to discuss fetal models Schizophrenia, postweaning social isolation and ended with In-Vitro animal models. The use of animal models to improve understanding of the neurochemical and structural CNS changes that precipitate development of Schizophrenia, rather than a focus on treating the symptoms, is a prerequisite to enable new more effective therapeutic strategies to be developed. Because of the complexity and ambiguity of gene-gene and gene-environment interactions in the aetiology of schizophrenia, the challenge of developing more reliable predictive animal models of this disorder, most likely through multiple early-life interventions, is still ongoing.

Increased levels of a pro-inflammatory IgG receptor in the midbrain of people with schizophrenia

BackgroundThere is growing evidence that neuroinflammation may contribute to schizophrenia neuropathology. Elevated pro-inflammatory cytokines are evident in the midbrain from schizophrenia subjects, findings that are driven by a subgroup of patients, characterised as a “high inflammation” biotype. Cytokines trigger the release of antibodies, of which immunoglobulin G (IgG) is the most common. The level and function of IgG is regulated by its transporter (FcGRT) and by pro-inflammatory IgG receptors (including FcGR3A) in balance with the anti-inflammatory IgG receptor FcGR2B. Testing whether abnormalities in IgG activity contribute to the neuroinflammatory abnormalities schizophrenia patients, particularly those with elevated cytokines, may help identify novel treatment targets.MethodsPost-mortem midbrain tissue from healthy controls and schizophrenia cases (n = 58 total) was used to determine the localisation and abundance of IgG and IgG transporters and receptors in the midbrain of healthy controls and schizophrenia patients. Protein levels of IgG and FcGRT were quantified using western blot, and gene transcript levels of FcGRT, FcGR3A and FcGR2B were assessed using qPCR. The distribution of IgG in the midbrain was assessed using immunohistochemistry and immunofluorescence. Results were compared between diagnostic (schizophrenia vs control) and inflammatory (high vs low inflammation) groups.ResultsWe found that IgG and FcGRT protein abundance (relative to β-actin) was unchanged in people with schizophrenia compared with controls irrespective of inflammatory subtype. In contrast, FcGRT and FcGR3A mRNA levels were elevated in the midbrain from “high inflammation” schizophrenia cases (FcGRT; p = 0.02, FcGR3A; p < 0.0001) in comparison to low-inflammation patients and healthy controls, while FcGR2B mRNA levels were unchanged. IgG immunoreactivity was evident in the midbrain, and approximately 24% of all individuals (control subjects and schizophrenia cases) showed diffusion of IgG from blood vessels into the brain. However, the intensity and distribution of IgG was comparable across schizophrenia cases and control subjects.ConclusionThese findings suggest that an increase in the pro-inflammatory Fcγ receptor FcGR3A, rather than an overall increase in IgG levels, contribute to midbrain neuroinflammation in schizophrenia patients. However, more precise information about IgG-Fcγ receptor interactions is needed to determine their potential role in schizophrenia neuropathology.

Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this modelsuch as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

On the classification of cerebral tumors: A tribute to Leonid Smirnov.

The corresponding member of the Academy of Medical Sciences of the USSR Professor Leonid Iosifovich Smirnov (1889-1955) authored several dozen publications on neuropathology of infections, schizophrenia, cerebral injuries, and brain tumors. Based on his study of pathology of gunshot head injuries during World WarII he suggested a doctrine of traumatic on traumatic brain disease. He was the author of the first Russian classification of cerebral tumors and had an impact on the development of neurooncology in the former USSR. The aim of this paper is to show the early development of modern neuropathology at the example of a leading Soviet neuropathologist in the first half of the 20th century and his relevance for modern classification of CNS tumors.

The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia

In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia.

Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients With Schizophrenia.

Accumulating evidence from clinical, genetic, and epidemiologic studies suggest that schizophrenia might be a neuronal development disorder. While oxysterols are important factors in neurodevelopment, it is unknown whether oxysterols might be involved in development of schizophrenia. The present study investigated the relationship between tissue-specifically originated oxysterols and risk of schizophrenia. A total of 216 individuals were recruited in this study, including 76 schizophrenia patients, 39 clinical high-risk (CHR) subjects, and 101 healthy controls (HC). We investigated the circulating levels of brain-specific oxysterol 24(S)-hydroxycholesterol (24OHC) and peripheral oxysterol 27-hydroxycholesterol (27OHC) in all participants and analyzed the potential links between the oxysterols and specific clinical symptoms in schizophrenic patients and CHR. Our data showed an elevation of 24OHC in both schizophrenia patients and CHR than that in HC, while a lower level of 27OHC in the schizophrenia group only. The ratio of 24OHC to 27OHC was only increased in the schizophrenic group compared with CHR and HC. For the schizophrenic patients, the circulating 24OHC levels are significantly associated with disease duration, positively correlated with the positive and negative syndrome total scores, while the 27OHC levels were inversely correlated with the positive symptom scores. Together, our data demonstrated the disruption of tissue-specifically originated cholesterol metabolism in schizophrenia and CHR, suggesting the circulating 24OHC or 24OHC/27OHC ratio might not only be a potential indicator for risk for schizophrenia but also be biomarkers for functional abnormalities in neuropathology of schizophrenia.

Neuroinflammation in Schizophrenia

Schizophrenia is a chronic debilitating mental illness. In many aspects, the neuropathology of schizophrenia is closely associated with neuroinflammation, especially microglial activation. Microglial hyperactivity, which is characterized by the predominant release of proinflammatory cytokines serves as the basis of the neuroinflammation hypothesis in schizophrenia. The enhanced inflammatory induce neuronal susceptibility to oxidative stress and trigger, glutamatergic synaptic dysregulation, especially in the mesolimbic and mesocortical pathways. Many in vitro studies, in vivo animal evidence, post-mortem examinations, neuroimaging evaluations with Positron Emission Tomography (PET), anti-inflammatory and antipsychotic use converge upon the central role of microglial activation and proinflammatory cytokines as common of features schizophrenia.

Multiple Neurodevelopmental Mechanisms of Schizophrenia in Patient-Derived Cerebral Organoids

Schizophrenia is presumed to be defined by neurodevelopmental pathology during fetal development. However, because of an inability to ethically study developing human neural tissue in utero, early arising schizophrenia neuropathology remains unknown and thus undefined. Resolving this matter would revolutionize our understanding of schizophrenia development, and define when pioneer neuropathology of schizophrenia actually begins.