Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies.

The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.

Tunneling nanotubes, a novel mode of tumor cell-macrophage communication in tumor cell invasion.

The interaction between tumor cells and macrophages is crucial in promoting tumor invasion and metastasis. In this study, we examined a novel mechanism of intercellular communication, namely membranous actin-based tunneling nanotubes (TNTs), that occurs between macrophages and tumor cells in the promotion of macrophage-dependent tumor cell invasion. The presence of heterotypic TNTs between macrophages and tumor cells induced invasive tumor cell morphology, which was dependent on EGF-EGFR signaling. Furthermore, reduction of a protein involved in TNT formation, M-Sec (TNFAIP2), in macrophages inhibited tumor cell elongation, blocked the ability of tumor cells to invade in 3D and reduced macrophage-dependent long-distance tumor cell streaming in vitro Using an in vivo zebrafish model that recreates macrophage-mediated tumor cell invasion, we observed TNT-mediated macrophage-dependent tumor cell invasion, distant metastatic foci and areas of metastatic spread. Overall, our studies support a role for TNTs as a novel means of interaction between tumor cells and macrophages that leads to tumor progression and metastasis.

Lithium increases cortical and subcortical volumes in subjects with bipolar disorder.

Bipolar disorder (BD) is a highly variable and burdensome disease for patients and caregivers. A BD diagnosis almost triples the likelihood of developing dementia as the disease progresses. Neurocognitive reserve appears to be one of the most important influences on lifelong functional outcomes and quality of life in BD. Though several prior studies have assessed the effects of lithium on regional gray and white matter volumes in this population, representative cohorts are typically middle-aged, have a more severe pathology, and are not as commonly assessed in the depressive phase (which represents the majority of most patients' lifespans outside of remission). Here we have shown that positive adaptations with lithium can be observed throughout the brain after only six weeks of monotherapy at low-therapeutic serum levels. Importantly, these results remove some confounders seen in prior studies (patients were treatment free at time of enrollment and mostly treatment naïve). This cohort also includes underrepresented demographics in the literature (young adult patients, mostly bipolar II, and exclusively in the depressed phase). These findings bolster the extensive body of evidence in support of long-term lithium therapy in BD, furthering the possibility of its expanded use to wider demographics.

A Retrospective Study of the Adjunctive Use of Gabapentin With Benzodiazepines for the Treatment of Benzodiazepine Withdrawal.

Benzodiazepine withdrawal is a widespread problem with potentially severe and deadly consequences. Currently, the only medications available for treating benzodiazepine withdrawal are short-acting and long-acting benzodiazepines. Identifying other drugs to help in treating benzodiazepine withdrawal is necessary. Gabapentin, an anxiolytic drug that is also used off-label to treat alcohol withdrawal, is a potential candidate for modulating benzodiazepine withdrawal. Using electronic records from a large inpatient psychiatric facility, a retrospective study of 172 patients presenting with benzodiazepine withdrawal was conducted to determine if the coincidental use of gabapentin for other medical conditions was associated with better outcomes of benzodiazepine withdrawal (N=57 gabapentin, N=115 no gabapentin). The primary outcomes were hospital length of stay and total amount of benzodiazepines given (lorazepam milligram equivalent). In this retrospective analysis of electronic medical record data, the patients experiencing benzodiazepine withdrawal who received gabapentin as an adjunct to the use of benzodiazepines were administered a smaller amount of benzodiazepines and had a shorter length of hospital stay relative to the comparison group who did not receive adjunctive gabapentin. These results suggest the potential use of gabapentin as an adjunct to the use of benzodiazepines for treating benzodiazepine withdrawal. The limitations of this study included a small sample size and variability in medication management strategies across the sample.

The role of lithium treatment on comorbid anxiety symptoms in patients with bipolar depression.

BACKGROUND: Comorbid anxiety is pervasive and carries an immense psychosocial burden for patients with bipolar disorder. Despite this, trials reporting anxiety-related outcomes in this population are uncommon, particularly with regards to monotherapies. METHODS: Patients (n = 31) with both bipolar I or II disorder in current depressive episodes were enrolled in a six-week, open-label, single-center trial assessing the efficacy of lithium monotherapy in treating symptoms depression and comorbid anxiety. Patients were mostly medication-free and lithium-naïve at baseline. RESULTS: Significant improvements in depression (HAMD) and anxiety (HAM-A) were observed at the six-week endpoint, with remission and response rates greater than 50%. There was a positive correlation between endpoint HAM-A scores and HAM-D scores, r = 0.80, (p < 0.01). Improvements were realized at low serum lithium concentrations (0.49 ± 0.20 mEq/L). LIMITATIONS: Lack of placebo control and small sample size warrants validation in larger randomized studies. CONCLUSIONS: Taken in the context of prior evidence, lithium may have an important role in treating comorbid anxiety in bipolar disorder, both as adjunct and monotherapy. Lower doses of lithium may provide equivalent efficacy and enhance tolerability and compliance.

Altered Antioxidant Defenses in Drug-Naive First Episode Patients with Schizophrenia Are Associated with Poor Treatment Response to Risperidone: 12-Week Results from a Prospective Longitudinal Study.

Abnormal redox regulation is thought to contribute to schizophrenia (SCZ). Accumulating studies have shown that the plasma antioxidant enzyme activity is closely associated with the course and outcome in antipsychotics-naïve first-episode (ANFE) patients with SCZ. The main purpose of this study was to investigate the effect of risperidone on oxidative stress markers in ANFE patients and the relationship between risperidone response and changes in oxidative stress markers. Plasma activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme, total antioxidant status (TAS), and malondialdehyde (MDA) levels were measured in 354 ANFE patients and 152 healthy controls. The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). Patients received risperidone monotherapy for 12 weeks and oxidative stress markers and PANSS were measured at baseline and at follow-up. Compared with healthy controls, the patients exhibited higher activities of SOD, CAT, and TAS levels, but lower MDA levels and GPx activity. A comparison between 168 responders and 50 non-responders at baseline and 12-week follow-up showed that GPx activity decreased in both groups after treatment. Moreover, GPx activity decreased less in responders and was higher in responders than in non-responders at follow-up. These results demonstrate that the redox regulatory system and antioxidant defense enzymes may have predictive value for the response of ANFE patients to risperidone treatment.

SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment.

Aligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in the in vivo context is still lacking. Here, we show that streaming tumor cells in vivo use collagen fibers with diameters below 3 µm. Employing 1D migration assays with matching in vivo fiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm-2.5 µm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cells in vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1 + 2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1 + 2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in an in vivo relevant 1D microenvironment.

The effect of phosphate accumulation on metal ion homeostasis in Saccharomyces cerevisiae.

Much of what is currently understood about the cell biology of metals involves their interactions with proteins. By comparison, little is known about interactions of metals with intracellular inorganic compounds such as phosphate. Here we examined the role of phosphate in metal metabolism in vivo by genetically perturbing the phosphate content of Saccharomyces cerevisiae cells. Yeast pho80 mutants cannot sense phosphate and have lost control of phosphate uptake, storage, and metabolism. We report here that pho80 mutants specifically elevate cytosolic and nonvacuolar levels of phosphate and this in turn causes a wide range of metal homeostasis defects. Intracellular levels of the hard-metal cations sodium and calcium increase dramatically, and cells become susceptible to toxicity from the transition metals manganese, cobalt, zinc, and copper. Disruptions in phosphate control also elicit an iron starvation response, as pho80 mutants were seen to upregulate iron transport genes. The iron-responsive transcription factor Aft1p appears activated in cells with high phosphate content in spite of normal intracellular iron levels. The high phosphate content of pho80 mutants can be lowered by mutating Pho4p, the transcription factor for phosphate uptake and storage genes. Such lowering of phosphate content by pho4 mutations reversed the high calcium and sodium content of pho80 mutants and prevented the iron starvation response. However, pho4 mutations only partially reversed toxicity from heavy metals, representing a novel outcome of phosphate dysregulation. Overall, these studies underscore the importance of maintaining a charge balance in the cell; a disruption in phosphate metabolism can dramatically impact on metal homeostasis.

The overlapping roles of manganese and Cu/Zn SOD in oxidative stress protection.

In various organisms, high intracellular manganese provides protection against oxidative damage through unknown pathways. Herein we use a genetic approach in Saccharomyces cerevisiae to analyze factors that promote manganese as an antioxidant in cells lacking Cu/Zn superoxide dismutase (sod1 Delta). Unlike certain bacterial systems, oxygen resistance in yeast correlates with high intracellular manganese without a lowering of iron. This manganese for antioxidant protection is provided by the Nramp transporters Smf1p and Smf2p, with Smf1p playing a major role. In fact, loss of manganese transport by Smf1p together with loss of the Pmr1p manganese pump is lethal to sod1 Delta cells despite normal manganese SOD2 activity. Manganese-phosphate complexes are excellent superoxide dismutase mimics in vitro, yet through genetic disruption of phosphate transport and storage, we observed no requirement for phosphate in manganese suppression of oxidative damage. If anything, elevated phosphate correlated with profound oxidative stress in sod1 Delta mutants. The efficacy of manganese as an antioxidant was drastically reduced in cells that hyperaccumulate phosphate without effects on Mn SOD activity. Non-SOD manganese can provide a critical backup for Cu/Zn SOD1, but only under appropriate physiologic conditions.