Enhanced long-term potentiation and impaired learning in mice lacking alternative exon 33 of CaV1.2 calcium channel

The CACNA1C (calcium voltage-gated channel subunit alpha 1 C) gene that encodes the CaV1.2 channel is a prominent risk gene for neuropsychiatric and neurodegenerative disorders with cognitive and social impairments like schizophrenia, bipolar disorders, depression and autistic spectrum disorders (ASD). We have shown previously that mice with exon 33 deleted from CaV1.2 channel (CaV1.2-exon 33−/−) displayed increased CaV1.2 current density and single channel open probability in cardiomyocytes, and were prone to develop arrhythmia. As Ca2+ entry through CaV1.2 channels activates gene transcription in response to synaptic activity, we were intrigued to explore the possible role of Cav1.2Δ33 channels in synaptic plasticity and behaviour. Homozygous deletion of alternative exon 33 resulted in enhanced long-term potentiation (LTP), and lack of long- term depression (LTD), which did not correlate with enhanced learning. Exon 33 deletion also led to a decrease in social dominance, sociability and social novelty. Our findings shed light on the effect of gain-of-function of CaV1.2Δ33 signalling on synaptic plasticity and behaviour and provides evidence for a link between CaV1.2 and distinct cognitive and social behaviours associated with phenotypic features of psychiatric disorders like schizophrenia, bipolar disorder and ASD.

Lithium and Erectile Dysfunction: An Overview

Lithium has been a mainstay of therapy for patients with bipolar disorders for several decades. However, it may exert a variety of adverse effects that can affect patients’ compliance. Sexual and erectile dysfunction has been reported in several studies by patients who take lithium as monotherapy or combined with other psychotherapeutic agents. The exact mechanisms underlying such side effects of lithium are not completely understood. It seems that both central and peripheral mechanisms are involved in the lithium-related sexual dysfunction. Here, we had an overview of the epidemiology of lithium-related sexual and erectile dysfunction in previous clinical studies as well as possible pathologic pathways that could be involved in this adverse effect of lithium based on the previous preclinical studies. Understanding such mechanisms could potentially open a new avenue for therapies that can overcome lithium-related sexual dysfunction and improve patients’ adherence to the medication intake.

Nrf2 Dysregulation in Major Depressive and Bipolar Disorders

Background: Major depressive disorder (MDD) and bipolar disorder (BPD) are two of the most important mental disorders that greatly impact different aspects of life. These conditions imply heavy health and economic burden and are heterogeneous in nature. Inflammation is reported as the etiology of mental disorders. Nrf2 transcription factor plays a key role in the defense mechanisms against inflammation and oxidative stress. So, this study aimed to evaluate the expression level of Nrf2 in MDD and BPD patients and compared it with healthy control subjects. Materials and Methods: In this study, real-time PCR was conducted to evaluate the expression level of Nrf2 in 100 MDD and 100 BPD patients compared to 100 healthy control subjects. Statistical analysis conducted on GraphPad Prism 8 and SPSS21 included ANOVA, Tukey’s test, receiver operating characteristic (ROC), and odds ratio. Results: Results suggest a significant downregulation of Nrf2 in these conditions compared to the control group. ROC curve analysis demonstrates Nrf2 as a biomarker of these psychiatric disorders. Conclusion: The elevated levels of reactive oxygen species and downregulation of detoxifying enzymes were observed in MDD and BPD, which can be associated with the downregulation of Nrf2. Concerning its role in inflammatory response pathways, alternation of Nrf2 expression can be associated with the pathology of these conditions.

Sleep disturbances in early clinical stages of psychotic and bipolar disorders: A meta-analysis

Objective: To provide a qualitative view and quantitative measure of sleep disturbances across and between early stages – clinical ultra high-risk and first episode – of psychotic and bipolar disorders. Methods: Electronic databases (PubMed, Cochrane, Embase, PsychINFO) were searched up to March 2021 for studies comparing sleep measures between individuals with an early stage and controls. Standard mean deviations (Cohen’s d effect sizes) were calculated for all comparisons and pooled with random-effects models. Chi-square tests were used for direct between-subgroups (ultra high-risk vs first episode) comparisons of standard mean deviations. The effects of age, sex ratio, symptoms and treatment were examined in meta-regression analyses. Results: A database search identified 13 studies that contrasted sleep measures between individuals with an early stage ( N = 537) and controls ( N = 360). We observed poorer subjective sleep quality (standard mean deviation = 1.32; 95% confidence interval, [1.01, 1.62]), shorter total sleep time (standard mean deviation =−0.44; 95% confidence interval, [−0.67, −0.21]), lower sleep efficiency (standard mean deviation = −0.72; 95% confidence interval, [−1.08, −0.36]), longer sleep onset latency (standard mean deviation = 0.75; 95% confidence interval, [0.45, 1.06]) and longer duration of wake after sleep onset (standard mean deviation = 0.49; 95% confidence interval, [0.21, 0.77]) were observed in early stages compared to controls. No significant differences were observed for any of the reported electroencephalographic parameters of sleep architecture. No significant between-subgroups differences were observed. Meta-regressions revealed a significant effect of the age and the antipsychotic status on subjective measures of sleep. Conclusion: The early stage population presents with significant impairments of subjective sleep quality continuity, duration and initiation. Systematic assessments of sleep in early intervention settings may allow early identification and treatment of sleep disturbances in this population.