Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Upregulated ECM genes and increased synaptic activity in Parkinson's human DA neurons with PINK1/ PRKN mutations.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but PD also affects the hippocampus and cortex, usually in its later stage. Approximately 15% of PD cases are familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PRKN. In vitro studies of these genetic mutations are needed to understand the neurophysiological changes in patients' neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from human induced pluripotent stem cells (hiPSCs) derived from two patients with a double mutation in their PINK1 and PRKN (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PRKN mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top two upregulated pathways in the mutant PD neurons. Our findings reveal that the phenotypes linked to PINK1 and PRKN mutations differ from those from other PD mutations, suggesting a unique interplay between these two mutations that drives different PD mechanisms.

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson's disease patients.

Parkinson's disease (PD) is a neurodegenerative disease with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, and gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, sporadic PD (sPD) patients, and PD patients with E326K-GBA1 mutations. Our results demonstrate reduced sodium currents and synaptic activity in DA neurons derived from PD patients with E326K-GBA1 mutations, suggesting a potential contribution to PD pathophysiology. We also observed distinct electrophysiological alterations in sPD DA neurons, which included a decrease in synaptic currents. RNA sequencing analysis revealed unique dysregulated pathways in sPD neurons and E326K-GBA1 neurons, further supporting the notion that molecular mechanisms driving PD may differ between PD patients. In agreement with our previous reports, Extracellular matrix and Focal adhesion pathways were among the top dysregulated pathways in DA neurons from sPD patients and from patients with E326K-GBA1 mutations. Overall, our study further confirms that impaired synaptic activity is a convergent functional phenotype in DA neurons derived from PD patients across multiple genetic mutations as well as sPD. At the transcriptome level, we find that the brain extracellular matrix is highly involved in PD pathology across multiple PD-associated mutations as well as sPD.

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations.

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genes GRIN2B, SHANK3, UBTF, as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3-5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.

The Efficacy of a Virtual Reality Exposure Therapy Treatment for Fear of Flying: A Retrospective Study.

Background: Fear of flying (FoF) is a phobia with 10-40% prevalence in the industrialized world. FoF is accompanied by severe economic, social, vocational, and emotional consequences. In recent years, virtual reality (VR)-based exposure therapy (VRET) for FoF has been introduced. Positive long-term efficacy of FoF-VRET has been reported by several studies, which, however, were limited by relatively small, non-representative samples and a lack of comparative pre/post functional efficacy outcome measures. Our objective was to evaluate the efficacy of a VRET treatment utilizing a large-scale VR system, experienced by a representative sample of self-referred individuals. Methods: We conducted a retrospective survey. Of 274 individuals who received the treatment (over a period of 3 years), 209 met inclusion/criteria, and 98 agreed to participate. We mainly collected information regarding flight activity before and after treatment relying on evidence such as boarding passes and flight tickets. The primary outcome measures were (1) number of flights per month (FpM) and (2) number of flight hours per month (FHpM). For each participant, these outcomes were computed for the post-treatment period (≥6 months after FoF-VRET) and the corresponding pre-treatment period. Results: FpM (mean ± SD) increased from 0.04 ± 0.06 to 0.16 ± 14 flights (p < 0.0001). FHpM rose from 0.19 ± 0.35 to 0.79 ± 0.87 h per month (p < 0.0001). Conclusion: These results are indicative of FoF-VRET treatment efficacy. Future studies should evaluate long-term maintenance of the treatment effect and thus identify the optimal frequency for delivery of periodic booster treatments.

Do journals instruct authors to address sex and gender in psychological science?

BACKGROUND: Sex and gender influence individuals' psychology, but are often overlooked in psychological science. The sex and gender equity in research (SAGER) guidelines provide instruction for addressing sex and gender within five sections of a manuscript (i.e., title/abstract, introduction, methods, results, and discussion) (Heidari et al., Res Integr Peer Rev 1:1-9, 2016). METHODS: We examined whether the 89 journals published by the American Psychological Association provide explicit instruction for authors to address sex and gender within these five sections. Both authors reviewed the journal instructions to authors for the words "sex," and "gender," and noted explicit instruction pertaining to these five sections. RESULTS: Only 8 journals (9.0%) instructed authors to address sex/gender within the abstract, introduction, and/or methods sections. No journals instructed authors to address sex and gender in the results or discussion sections. CONCLUSION: These journals could increase sex/gender equity and improve the reproducibility of psychological science by instructing authors to follow the SAGER guidelines.