Prefrontal Cortex In Schizophrenia Research Articles

Increased pituitary adenylate cyclase-activating peptide genes expression in the prefrontal cortex in schizophrenia in relation to suicide.

Pituitary adenylate cyclase-activating peptide (PACAP) is a stress-related neuropeptide that is produced in several brain areas. It acts by 3 receptors: PACAP type-1 (PAC1), vasoactive intestinal peptide (VIP) -1 and -2 (VPAC1 and 2). Data on polymorphisms in PACAP and PAC1 indicate a relationship of the PACAP system with schizophrenia (SCZ). The prefrontal cortex was chosen to measure PACAP-gene related expression changes, since this is a central structure in the symptoms of schizophrenia (SCZ). We investigated alterations in the expression of the PACAP-related genes by qPCR in the human dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of 35 SCZ patients and 34 matched controls in relation to SCZ, suicide, gender and medication. The ACC revealed an upregulation in PACAP, PAC1, VPAC1 and VPAC2 in SCZ suicide (S) completers compared to controls. An increase in PACAP, VPAC1 and VPAC2 expression was also present in the ACC in SCZ-S compared to SCZ patients who died naturally (SCZ-N). In the DLPFC, an increase in PAC1 was found in SCZ-N patients compared to SCZ-S and controls. Moreover, an increase in all PACAP-related genes was present in SCZ-N male patients compared to SCZ-N females. Concluding, expression changes were found in PACAP-related genes in relation to SCZ, suicide and gender. In particular, there was a higher PACAP-related gene expression in SCZ patients in the ACC in relation to suicide and in DLPFC in relation to SCZ. These findings suggest a potential link between PACAP and the pathophysiology of SCZ and suicide. Further research is needed to understand the functional significance and potential clinical applications of these changes.

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia

Background: schizophrenia is associated with neuroinflammation and dysregulation of the immune system involving microglia. The study of microglial reactivity in schizophrenia is at an early stage. The results of neuroimaging and postmortem studies are contradictory. Aim of the study: to analyze and summarize the results of morphometric studies of the microglial reactivity at the ultrastructural level in postmortem prefrontal cortex in schizophrenia compared to healthy controls. Material and methods: the study was performed in layer 5 of the prefrontal cortex in 21 cases of schizophrenia and 20 control cases using transmission electron microscopy and morphometry. Results and conclusion: we found that chronic schizophrenia is characterized by a combination of signs of activation, progressive dystrophy and accelerated aging of microglia. The reactivity of microglia in schizophrenia is associated with age, the age of onset of the disease, the duration of the disease and the type of course of the disease, which indicates the participation of microglia in the pathological process in schizophrenia. Damage and deficit mitochondria and the disturbance of energy metabolism can play a key role in microglial dysfunction in schizophrenia.

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modelling

Objectives Schizophrenia is characterised by deficits across multiple cognitive domains and altered glutamate related neuroplasticity. The purpose was to investigate whether glutamate deficits are related to cognition in schizophrenia, and whether glutamate-cognition relationships are different between schizophrenia and controls. Methods Magnetic resonance spectroscopy (MRS) at 3 Tesla was acquired from the dorsolateral prefrontal cortex (dlPFC) and hippocampus in 44 schizophrenia participants and 39 controls during passive viewing visual task. Cognitive performance (working memory, episodic memory, and processing speed) was assessed on a separate session. Group differences in neurochemistry and mediation/moderation effects using structural equation modelling (SEM) were investigated. Results Schizophrenia participants showed lower hippocampal glutamate (p = .0044) and myo-Inositol (p = .023) levels, and non-significant dlPFC levels. Schizophrenia participants also demonstrated poorer cognitive performance (p < .0032). SEM-analyses demonstrated no mediation or moderation effects, however, an opposing dlPFC glutamate-processing speed association between groups was observed. Conclusions Hippocampal glutamate deficits in schizophrenia participants are consistent with evidence of reduced neuropil density. Moreover, SEM analyses indicated that hippocampal glutamate deficits in schizophrenia participants as measured during a passive state were not driven by poorer cognitive ability. We suggest that functional MRS may provide a better framework for investigating glutamate-cognition relationships in schizophrenia.

Localization and Diagnostic Specificity of Glutamic Acid Decarboxylase Transcript Alterations in the Dorsolateral Prefrontal Cortex in Schizophrenia

BackgroundWorking memory (WM) deficits in schizophrenia are thought to reflect altered inhibition in the dorsolateral prefrontal cortex (DLPFC). This interpretation is supported by findings of lower transcript levels of the 2 enzymes, GAD67 and GAD65, which mediate basal and activity-dependent GABA (gamma-aminobutyric acid) synthesis, respectively. However, the relative magnitude, location within the depth of the DLPFC, and specificity to the disease process of schizophrenia of alterations in GAD67 and/or GAD65 remain unclear. MethodsLevels of GAD67 and GAD65 messenger RNAs (mRNAs) in superficial (layers 2/superficial 3) and deep (deep layer 6/white matter) zones of the DLPFC were quantified by quantitative polymerase chain reaction in subjects with schizophrenia (n = 41), major depression (n = 42), or bipolar disorder (n = 39) and unaffected comparison (n = 43) subjects. ResultsRelative to the unaffected comparison group, GAD67 and GAD65 mRNA levels in the schizophrenia group were lower (p = .039, effect size = −0.69 and p = .027, effect size = −0.72, respectively) in the superficial zone but were unaltered in the deep zone. In the major depression group, only GAD67 mRNA levels were lower and only in the superficial zone (p = .089, effect size = 0.70). No differences were detected in the bipolar disorder group. Neither GAD67 nor GAD65 mRNA alterations were explained by psychosis, mood disturbance, or common comorbid factors. ConclusionsAlterations in markers of GABA synthesis demonstrated transcript, DLPFC zone, and diagnostic specificity. Given the dependence of WM on GABA neurotransmission in the superficial DLPFC, our findings suggest that limitations to GABA synthesis in this location contribute to WM impairments in schizophrenia, especially during demanding WM tasks, when GABA synthesis requires the activity of both GAD67 and GAD65.

Relation between spectral entropy modulation and cortical reactivity of the dorsolateral prefrontal cortex in schizophrenia and controls: a TMS-EEG study

Relation between spectral entropy modulation and cortical reactivity of the dorsolateral prefrontal cortex in schizophrenia and controls: a TMS-EEG study

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia with Different Types of Course

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia with Different Types of Course

P537. Metabolomic Measures of Oxidative Stress in the Dorsal and Ventral Striatum and Dorsolateral Prefrontal Cortex in Schizophrenia

Oxidative stress is proposed to contribute to schizophrenia (SZ) pathophysiology. Some oxidant sources, such as mitochondria, are ubiquitous in the brain, but others, such as dopamine degradation, are brain region-dependent. SZ is associated with excess striatal dopamine that is most pronounced in dorsal striatum (DS) relative to ventral striatum (VS) and is not present in dorsolateral prefrontal cortex (DLPFC). We investigated the possibility that markers of oxidative stress and damage are most pronounced in DS relative to VS and DLPFC in SZ subjects.

N-Methyl-d-Aspartate receptor and inflammation in dorsolateral prefrontal cortex in schizophrenia

Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor — particularly the ratio of GluN2A and GluN2B subunits — in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect ‘functional’ NMDARs ([3H]MK-801), GluN1-coupled-GluN2A subunits ([3H]CGP-39653), and GluN1-coupled-GluN2B subunits ([3H]Ifenprodil). Quantitative RT-PCR was used to measure NMDAR subunit transcripts (GRIN1, GRIN2A and GRIN2B). The ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were calculated as an index of putative NMDAR composition. We found: 1) GluN2A binding, and 2) the ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were lower in schizophrenia cases versus controls (p < 0.05), and 3) lower GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNA ratios were exaggerated in the high inflammation/schizophrenia subgroup compared to the low inflammation/control subgroup (p < 0.05). No other NMDAR-related indices were significantly changed in the high inflammation/schizophrenia subgroup. This suggests that neuroinflammation may alter NMDAR stoichiometry rather than targeting total NMDAR levels overall, and future studies could aim to determine if anti-inflammatory treatment can alleviate this aspect of NMDAR-related pathology.

Reduced number of satellite oligodendrocytes of pyramidal neurons in layer 5 of the prefrontal cortex in schizophrenia.

Neuroimaging, genetic and molecular biological studies have shown impaired intra-cortical myelination in patients with schizophrenia, particularly in the prefrontal cortex. Previously we reported a significant deficit of oligodendrocytes and oligodendrocyte clusters in layers 3 and 5 of the prefrontal cortex, Brodmann area 10 (BA10) in schizophrenia. In this current study, we investigate the number of oligodendrocyte satellites (Sat-Ol) per pyramidal neuron in layer 5 of BA10 in schizophrenia (n = 17) as compared to healthy controls (n = 20) in the same section collection as previously used to study the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters. We find a significant reduction (-39%, p < 0.001) in the number of Sat-Ol per neuron in schizophrenia as compared to the control group. The number of Sat-Ol per neuron did not correlate with the Nv of oligodendrocytes or with the Nv of oligodendrocyte clusters. Our previous studies of the inferior parietal lobule (BA39 and BA40), demonstrated significant decrease of the number of Sat-Ol only in patient subgroups with poor and fair insight. Additionally, correlation pattern between number of Sat-Ol and Nv of oligodendrocytes and oligodendrocyte clusters was similar between the two functionally interconnected cortical areas, BA10 and BA40, whereas in BA39, strong significant correlations were revealed between the number of Sat-Ol and Nv of oligodendrocyte clusters (0.9 ≤ R ≥ 0.66; p < 0.001). These data suggest that that specific features of Sat-Ol alterations patterns may be associated with specific activity-driven plasticity of corresponding networks in the brain of people with schizophrenia.

Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia.

Microglial activation has been proposed to contribute to the pathogenesis of schizophrenia. The present study addressed the questions of whether microglial reactivity is involved in the course of schizophrenia and is associated with aging. Transmission electron microscopy and morphometry were applied to estimate microglial density and ultrastructural parameters in layer 5 of the prefrontal cortex (BA10) in postmortem 21 chronic schizophrenia and 20 healthy control cases. A significant increase in microglial density was found in the schizophrenia group (+20 %), in young group (≤50 y.o.), in shorter duration of disease (≤26 yrs.) group, in early age at onset of disease (≤ 21 y.o.) group as compared to controls (p < 0.05) and in young schizophrenia group as compared to both young and elderly (>50 y.o.) controls (p < 0.05). Volume fraction (Vv) of mitochondria was significantly lower and area of lipofuscin granules was significantly higher in young and elderly schizophrenia groups as compared to young and elderly controls. Vv of lipofuscin granules strongly positively correlated with age and duration of disease in the schizophrenia group. Vv and the number (N) of lipofuscin granules were higher in longer duration (>26 yrs.) group as compared to shorter duration group (p < 0.01). Vv and N of vacuoles were increased in longer duration group as compared to controls (p < 0.01). The study provides evidence for microgliosis associated with age, duration of disease and age at onset of disease, progressive dystrophy and accelerated aging of microglia in gray matter of the prefrontal cortex in schizophrenia.

Transcriptomic and Metabolomic Measures of Oxidative Stress in the Dorsolateral Prefrontal Cortex in Schizophrenia

Oxidative stress in the brain occurs when antioxidant systems, such as reduced glutathione (GSH), are overwhelmed by pro-oxidant species, resulting in damage to fundamental cellular components and impaired neuronal functioning. Insufficient GSH is proposed as a pathogenic mechanism contributing to cortical neuronal dysfunction in schizophrenia (SZ). To investigate this possibility, we first quantified markers of the glutathione system and oxidative damage to lipids utilizing quantitative mass spectrometry in the dorsolateral prefrontal cortex (DLPFC) of SZ subjects. Next, we performed transcriptomic analysis of a gene set indexing multiple antioxidant systems in DLPFC gray matter in SZ.

Involvement of the nuclear factor-\u03baB transcriptional complex in prefrontal cortex immune activation in bipolar disorder

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.

Concordance of Immune-Related Markers in Lymphocytes and Prefrontal Cortex in Schizophrenia.

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (Pnominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (Pnominal < .01 and |log2 FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

Impairments to Oligodendrocyte Clustering in the Supra- and Infragranular Layers of Field 10 of the Prefrontal Cortex in Schizophrenia

Objectives. Intravital studies have shown that alterations to myelination in the gray matter of the cortex in schizophrenia are the most marked in the prefrontal cortex. The authors have previously observed a decrease in the number density of oligodendrocytes (ND OL) in layers 3 and 5 of field 10 of the prefrontal cortex in schizophrenia. Proliferation of oligodendrocyte precursors in the brains of adult animals and humans is known to lead to the formation of oligodendrocyte clusters (OLC) and this process is linked with function-dependent axon myelination. The aim of the present work was to determine ND OLC and the ratio of ND OLC to ND OL in the functionally diverse supra- and infragranular layers of field 10 in health and schizophrenia. Materials and methods. ND OLC was determined in layers 3a, 3b, and 3c (supragranular) and 5a (infragranular) of field 10 using an optical dissector on Nissl-stained sections in 17 cases of schizophrenia and 20 people without mental disorders. Results and conclusions. Decreases in ND OLC were seen in both the supra- (by 32%, p < 0.02, Duncan test) and the infragranular (by 50%, p < 0.001) sublayers of field 10 in schizophrenia as compared with the control group. A decrease in the ND OLC/ND OL ratio was significant only for sublayers 2a (p = 0.015) and 5a (p < 0.001). In the control group, ND OLC showed a significant correlation with ND OL in sublayers 3b, 3c, and 5a (R ≥ 0.59, p ≤ 0.006), while in the schizophrenia group only layer 5a showed a persisting positive correlation (R = 0.8, p = 0.00001) between measures. A deficit of OLC in field 10 in schizophrenia may be due to impaired proliferation and/or differentiation of OL precursors. The nature of the interaction between ND OLC and ND OL presumptively depends on the characteristics of the connections between the corresponding cortical sublayers and their changes in schizophrenia.

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study

Trans-cranial magnetic stimulation (TMS) can noninvasively modulate specific brain regions to dissipate symptoms in treatment-resistant schizophrenia (TRS). Citing impaired resting state connectivity between cerebellum and prefrontal cortex in schizophrenia, we aimed to study the effect of intermittent theta burst stimulation (iTBS) targeting midline cerebellum in TRS subjects on a randomized rater blinded placebo control study design. In this study, 36 patients were randomly allocated (using block randomization method) to active and sham iTBS groups. They were scheduled to receive ten iTBS sessions, two per day (total of 1200 pulses) for 5 days in a week. The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Schizophrenia Cognition Rating Scale (SCoRS), Simpson-Angus Extrapyramidal Side Effects Scale (SAS), and Clinical Global Impression (CGI) were assessed at baseline, after last session, and at 2 weeks post-rTMS. Thirty patients (16 and 14 in active and sham groups) completed the study. Intention to treat analysis (ITT) using mixed (growth curve) model analysis was conducted. No significant group (active vs sham) × time (pretreatment–end of 10th session–end of 2 weeks post iTBS) interaction was found for any of the variable. No major side effects were reported. Our study fails to show a significant effect of intensive cerebellar iTBS (iCiTBS) on schizophrenia psychopathology, cognitive functions, and global improvement, compared with sham stimulation, in treatment resistant cases. However, we conclude that it is safe and well tolerated. Trials using better localization technique with large sample, longer duration, and better dosing protocols are needed.Electronic supplementary materialThe online version of this article (10.1007/s12311-020-01193-9) contains supplementary material, which is available to authorized users.

Коррекция нарушений нейрональных гомеостатических механизмов при нервно-психических заболеваниях как вероятное направление медикаментозного воздействия

The improvement of drug therapy for a number of neuropsychiatric diseases requires the search for new directions of action in comparison with those currently used. Most of the drugs used affect molecular targets that modulate interstructural (interneuronal) interactions. Influencing the deeper processes of synaptic and neuronal homeostasis may be a new direction in the treatment of these diseases. This review examines the mechanisms of homeostatic plasticity of synaptic transmission and electrical excitability of neurons, which balance each other and stabilize the functioning of neurons and neural networks. The first type of homeostatic plasticity is regulated by the intracellular Ca2+ concentration and the activity of protein kinases, and the second one - by membrane density of voltage-dependent ionic channels. Analysis of literature data shows that alterations in some neuro-psychiatric diseases reveal disorders of homeostatic plasticity more often in terms of monodirectional alterations of synaptic impacts and neuronal electrical excitability. Thus, mainly in preclinical studies, it was revealed that stress-induced depressive disorders of behavior are accompanied by a unidirectional increase in pyramidal neurons of 2/3 layers of the prefrontal cortex of rodents, or a weakening in neurons of the 5th layer of synaptic drive and electrical excitability. Similar disorders of homeostatic plasticity were observed by other authors in pyramidal neurons of the dorsolateral prefrontal cortex in schizophrenia, depending on the prevalence of positive or negative symptoms. In chronic neuropathic pain, an increase in the excitability of peripheral neurons of the spinal / trigeminal ganglia, neurons of the dorsal horns, and cortical neurons and an increase in incoming synaptic influences were revealed. The observed disturbances were accompanied by changes in the density of ion channels in neuronal membranes. The peculiarities of the distribution and biophysical properties of voltage-dependent potassium channels allow us to consider them as a probable molecular target for the correction of disorders of homeostatic plasticity.

Altered levels of immune cell adhesion molecules are associated with memory impairment in schizophrenia and healthy controls

Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in “high inflammation” schizophrenia compared to both “high” and “low inflammation” controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.

Diminished levels of the chemokine fractalkine in post-mortem prefrontal cortex in schizophrenia but not bipolar disorder

Objectives Though the pathophysiology underlying schizophrenia (SCZ) and bipolar disorder (BD) is not fully understood, immune function may be dysregulated, with microglia, the brain’s resident immune cells, implicated in this process. Signalling between the neuronal chemokine fractalkine (CX3CL1) and its microglial receptor CX3CR1 facilitates neuron-microglia interactions, influencing microglial activation and synaptic function. As such, alterations in fractalkine signalling may contribute to immune and synaptic alterations observed in SCZ and BD. Methods Protein and mRNA expression of fractalkine, CX3CR1, and a disintegrin and metalloproteinase 10 (ADAM10), a sheddase that cleaves fractalkine, were quantified in post-mortem frontal cortex from individuals with SCZ (n = 35), BD (n = 34), and matched controls (n = 35) using immunoblotting and droplet digital PCR. In addition, the relationship between fractalkine pathway members and levels of the pre-synaptic protein SNAP-25 was examined. Results Fractalkine protein levels were significantly lower in SCZ relative to controls. Expression of members of the fractalkine signalling pathway was unchanged in BD. CX3CR1 protein levels were significantly correlated with SNAP-25 levels. Conclusions The observed deficit in fractalkine protein levels in SCZ is consistent with impaired neuron-microglia crosstalk in this disorder. Furthermore, our data are suggestive of an aberrant association between microglial function and synaptic density in SCZ.

Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia.

Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.