Tolerability of perampanel: A retrospective study at the department of psychiatry.

PURPOSE: We aimed to identify factors that contribute to the discontinuation of perampanel. METHODS: We retrospectively analyzed patients with epilepsy at the Department of Psychiatry, Hokkaido University Hospital. We evaluated the factors contributing to perampanel discontinuation as primary outcomes using Cox proportional hazards regression. Then, we explored the components contributing to the primary outcomes using logistic regression analysis. RESULTS: A total of 118 patients were included, 44.9% of whom discontinued participation, 22.0% had intellectual disability, and 23.7% had a psychiatric disorder other than intellectual disability. Adverse effects occurred in 65% of the patients, 23.7% had psychiatric adverse effects (PAE), and 49.2% had common adverse effects (CAE). The effect of PER to suppress seizures was confirmed in 65.3% of them. Discontinuation was influenced by non-response (Hazard Ratio (HR) 6.70, 95% Confidence Interval (CI) 3.42-13.1), the occurrence of PAE (HR 3.68, 95% CI 1.89-7.16), CAE (HR 1.90, 95% CI 1.06-3.41), and comorbid psychiatric disorders (HR 2.35, 95% CI 1.21-4.59). Moreover, comorbid intellectual disability correlated with a low risk of PAE (OR 0.19, 95% CI 0.04-0.89). CONCLUSION: The discontinuation of perampanel is influenced by poor efficacy and the occurrence of common/psychiatric adverse effects. The discontinuation of perampanel is influenced by poor efficacy and the occurrence of common/psychiatric adverse effects. Consideration of factors contributing to perampanel discontinuation may assist in determining the indication for perampanel treatment.

Interpersonal Sensitivity as a Mediator of the Effect of Childhood Parenting Quality on Depressive Symptoms.

ABSTRACT: The aim of this study was to analyze whether interpersonal sensitivity mediates the effect of qualitative parenting characteristics experienced during childhood on the appraisal of life experiences and depression severity during adulthood in adult community volunteers. A total of 404 Japanese adult volunteers answered the following four self-report questionnaires: Parental Bonding Instrument, Interpersonal Sensitivity Measure, Life Experiences Survey, and Patient Health Questionnaire-9. Structural equation modeling was performed to analyze whether childhood parenting quality increases depressive symptom severity through interpersonal sensitivity, which then affects the appraisal of recent life events. In the two structural equation models, inadequate care and excessive overprotection received during childhood were associated with the negative evaluation of life experiences and depression severity in adulthood through high interpersonal sensitivity. Our findings indicate interpersonal sensitivity as a mediator of the effect of inadequate care and excessive overprotection experienced in childhood on the negative evaluation of life experiences and depression severity in adulthood.

Outpatient visit behavior in patients with epilepsy: Generalized Epilepsy is more frequently non-attendance than Focal Epilepsy.

BACKGROUND: Patients with epilepsy (PWE), especially those with Idiopathic Epilepsy (GE), are at a high risk of disadvantage caused by non-adherence. It has been suggested that medical visit behavior may be a surrogate indicator of medication adherence. We hypothesized that patients with IGE would adhere poorly to visits. METHODS: This was a retrospective study of PWE who visited the Department of Psychiatry and Neurology at Hokkaido University Hospital between January 2017 and December 2019. Demographic and clinical information on PWE were extracted from medical records and visit data from the medical information system. Non-attendance of outpatient appointments was defined as "not showing up for the day of an appointment without prior notice." Mixed-effects logistic regression analysis was conducted with non-attendance as the objective variable. RESULTS: Of the 9151 total appointments, 413 were non-attendances, with an overall non-attendance rate of 4.5%. IGE was a more frequent non-attendance than Focal Epilepsy (FE) (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.17-3.21; p = 0.010). History of public assistance receipt was associated with higher non-attendance (OR 2.04; 95% CI 1.22-3.43; p = 0.007), while higher education (OR 0.64; 95% CI 0.43-0.93; p = 0.021) and farther distance to a hospital (OR 0.33; 95% CI 0.13-0.88; p = 0.022), and higher frequency of visits (OR 0.18; 95% CI 0.04-0.86; p = 0.031) were associated with fewer non-attendances. In a subgroup analysis of patients with GE, women were associated with fewer non-attendance (OR 0.31; 95% CI 0.14-0.72; p = 0.006). CONCLUSIONS: GE was more frequent in the non-attendance group than in the FE group. Among patients with GE, females were found to have non-attendance less frequently; however, there was no clear difference in the odds of non-attendance between Juvenile Myoclonic Epilepsy (JME) and IGE other than JME.

Neurobiological correlation between phosphorylated tau and mood symptoms in memory clinic patients.

BACKGROUND: Alzheimer's disease (AD) dementia and mild cognitive impairment are characterised by impaired cognition accompanied by neuropsychiatric symptoms (NPS) relating to mood, including depression, anxiety, and apathy. However, the utility of AD biomarkers for predicting mood symptoms of NPS remains controversial. Herein, we analyzed the relationship between phosphorylated tau (p-tau) and depression, anxiety, and apathy of NPS. We also examined the influence of genetic factors such as apolipoprotein E (APOE) ε4 on these relationships. METHODS: We conducted a cross-sectional survey in older patients (n = 122) with normal cognition (n = 12), mild cognitive impairment (n = 46), and AD (n = 64) strictly diagnosed by the board of psychiatrists and neurologists of Hokkaido University. NPS of the patients were assessed using the Neuropsychiatric Inventory Questionnaire (NPI). All patients also received a lumbar puncture to obtain cerebral spinal fluid for assessment of p-tau. The inverse probability weighting method was used to adjust for demographic differences between the p-tau present group and the p-tau absent group. RESULTS: There was an association between p-tau accumulation and decreased incidence of depression and apathy. APOE ε4 non-carriers also showed a trend toward a negative association between p-tau and depression, which was not evident in APOE ε4 carriers. CONCLUSIONS: We provide new evidence for a negative correlation between p-tau and depression and apathy of NPS, which may be influenced by APOE ε4. Future longitudinal studies are required to confirm the utility of p-tau for predicting the course of mood symptoms in patients with cognitive decline.

Cognitive complaints mediate the influence of sleep disturbance and state anxiety on subjective well-being and ill-being in adult community volunteers: a cross sectional study.

BACKGROUND: Sleep disturbance, state anxiety, and cognitive complaints (CCs) have been recognized as important issues in public health. Although the mediating role of CCs has been proposed, their role in the relationships between sleep disturbance, state anxiety, and subjective well-being (SWB) and subjective ill-being (SIB) are not yet fully understood. This study used path analyses to investigate whether CCs mediate these relationships. METHODS: The study recruited 523 Japanese adult volunteers using convenience sampling. Participants completed the Pittsburgh Sleep Quality Index, State-Trait Anxiety Inventory (Form Y), Cognitive Complaints in Bipolar Disorder Rating Assessment, and Subjective Well-Being Inventory to evaluate sleep disturbance, state anxiety, CCs, and SWB and SIB, respectively. Path analyses were conducted to assess the mediating effects of CCs. RESULTS: The path analyses showed significant indirect associations of sleep disturbance and state anxiety with SWB (p = 0.024 and p = 0.012) and SIB (p < 0.001 and p < 0.001), respectively, mediated by CCs. Furthermore, there were significant indirect associations of sleep disturbance with CCs (p < 0.001), SWB (p < 0.001), and SIB (p < 0.001), via state anxiety, respectively. CONCLUSIONS: This study suggests that CCs mediate the associations of sleep disturbance and state anxiety with SWB and SIB, respectively, in adult community volunteers. To address SWB and SIB associated with sleep disturbance and state anxiety, evaluating CCs may be useful in public mental health. Our findings will encourage health care workers to assess CCs more systematically. Future studies may need to target CCs to develop interventions for SWB and SIB.

Subjects with bipolar disorder showed different reward system activation than subjects with major depressive disorder in the monetary incentive delay task.

BACKGROUND: Differentiating between bipolar disorder (BD) and major depressive disorder (MDD) during the depressive episode is an important clinical challenge. Reward system abnormalities have received much attention as one of the biological underpinnings of BD and MDD, but few studies have directly compared these abnormalities in remitted and depressed states. METHODS: This was a functional MRI study using the Monetary Incentive Delay task in 65 patients (BD [n = 33], MDD [n = 32]) and 33 healthy controls (HC). Regions of interest (ROI) analysis with 21 ROIs related to reward anticipation and 17 ROIs related to gain outcome were implemented, as well as whole-brain analysis. The difference in the dimensional effect of depression on brain activation was also examined. RESULTS: Relative to the HC group, BD patients showed significantly decreased activation during reward anticipation in the anterior cingulate cortex, anterior insula (AI), and putamen, and MDD patients showed significantly decreased activation in the AI and brainstem. The dimensional effect of depression severity showed a trend-level difference between BD and MDD in the right brainstem and left AI. CONCLUSIONS: The current study showed a possible differential effect of depression on the reward system between MDD and BD. Further studies on reward systems might offer reliable markers to distinguish between MDD and BD patients in the depressive phase.

White matter microstructural alterations across four major psychiatric disorders: mega-analysis study in 2937 individuals.

Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.

TEMPS-A (short version) plays a supplementary role in the differential diagnosis between major depressive disorder and bipolar disorder.

AIM: Early differential diagnosis between patients with major depressive disorder (MDD) and bipolar disorder (BD), and subsequently providing appropriate treatments are essential. There has been increased interest regarding the association between affective temperaments and mood disorder diagnosis. Our aim was to analyze the diagnostic validity of affective temperaments assessed by the short version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), in mood disorder patients. METHODS: Inpatients with MDD (n = 146) or BD (n = 128) completed the short version of TEMPS-A, and their depressive and manic symptom severities were evaluated. Data of MDD and BD patients were compared by univariable and multivariable analyses. RESULTS: Of the five affective temperament dimensions, substantially higher hyperthymic, irritable, and cyclothymic temperament scores were found in BD patients than in MDD patients. Using a multivariable logistic regression model built using the severities of depressed and manic conditions, and the five affective temperament subscale scores as independent variables, we identified two factors statistically associated with BD diagnosis (anxious temperament and cyclothymic temperament). The recommended cutoff point for the 12 items evaluating cyclothymic temperament to differentiate BD from MDD was 8 or more 'True' items (sensitivity: 35.9%, specificity: 87.7%). LIMITATIONS: Our design was cross-sectional, and therefore, there was a possibility of longitudinal diagnostic conversion of patients from MDD to BD. CONCLUSION: Cyclothymic and anxious temperaments on the short version of TEMPS-A, identified as diagnostic differentiating factors between MDD and BD, may play supplementary roles in the early identification of BD.

Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine.

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.

Distinctive Neuroanatomical Substrates for Depression in Bipolar Disorder versus Major Depressive Disorder.

No neuroanatomical substrates for distinguishing between depression of bipolar disorder (dBD) and major depressive disorder (dMDD) are currently known. The aim of the current multicenter study was to identify neuroanatomical patterns distinct to depressed patients with the two disorders. Further analysis was conducted on an independent sample to enable generalization of results. We directly compared MR images of these subjects using voxel-based morphometry (VBM) and a support vector machine (SVM) algorithm using 1531 participants. The VBM analysis showed significantly reduced gray matter volumes in the bilateral dorsolateral prefrontal (DLPFC) and anterior cingulate cortices (ACC) in patients with dBD compared with those with dMDD. Patients with the two disorders shared small gray matter volumes for the right ACC and left inferior frontal gyrus when compared with healthy subjects. Voxel signals in these regions during SVM analysis contributed to an accurate classification of the two diagnoses. The VBM and SVM results in the second cohort also supported these results. The current findings provide new evidence that gray matter volumes in the DLPFC and ACC are core regions in displaying shared and distinct neuroanatomical substrates and can shed light on elucidation of neural mechanism for depression within the bipolar/major depressive disorder continuum.

A propensity score matching analysis for cardio metabolic risk of antipsychotics in patients with schizophrenia using Japanese claims data.

BACKGROUND: The aim of this study was to evaluate the cardio-metabolic risk in schizophrenia patients treated by atypical antipsychotic drugs compared with that in those treated without atypical antipsychotic drugs using a nationwide insurance claims database and medical examination database in Japan. METHODS: Eligible patients were defined as those meeting the following two criteria: (i) A diagnosis of schizophrenia (ICD-10 code: F20) was made between 1 January 2005 and 31 December 2017, with data available for at least 6 months before the diagnosis was made (index month), and (ii) health check-up data were available within ±3 months of the index month. The primary endpoint was changes in cardio-metabolic risk based on the Suita score at 1 year, and the secondary endpoints were changes in medical examination data related to cardio-metabolic risk (total cholesterol [TC], triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, body mass index [BMI], and hemoglobin A1c) at 1 year. The primary endpoint was evaluated by multivariate analysis, with the cumulative chlorpromazine equivalent amount and the baseline Suita score added as covariates. RESULTS: One-hundred eighty five pairs of propensity score (PS)-matched patients were evaluated. Patients receiving atypical antipsychotic drugs exhibited a greater change in the Suita score and a risk of coronary heart disease based on the Suita score of 0.530 and 0.098%, respectively, than patients not receiving atypical antipsychotic drugs, but there was no significant difference (p = 0.412 and 0.610). The significant changes in TC and BMI were determined as 6.525 mg/dL and 0.380 kg/m2 greater, respectively, in patients treated with atypical antipsychotic drugs (p = 0.037 and 0.011). CONCLUSIONS: There were no significant increases in changes in the Suita score at 1 year by treatment with atypical antipsychotic drugs compared with treatment without atypical antipsychotic drugs. However, the TC and BMI were significantly higher in patients treated with atypical antipsychotic drugs.

Maternal cerebellar gray matter volume is associated with daughters' psychotic experience.

AIM: A substantial portion of children and adolescents show subthreshold psychotic symptoms called psychotic experience (PE). Because PE shares its biological and environmental risk factors with psychotic spectrum disorders, parental neuroanatomical variation could reflect a heritable biological underpinning of PE that may predict an offspring's PE. METHODS: A total of 94 participants from 35 families without a diagnosis of major neuropsychiatric disorders were examined, including 14 mother-daughter, 17 mother-son, 12 father-daughter, and 16 father-son dyads. An offspring's PE was assessed with the Atypicality subscale of the Behavior Assessment System for Children - 2nd Edition, Self-Report of Personality form (BASCaty). We examined correlations between voxel-by-voxel parental gray matter volume and their offspring's BASCaty score. RESULTS: Maternal cerebellar gray matter volume using voxel-based morphometry was positively correlated with their daughters' BASCaty scores. The findings were significant in a more robust approach using cerebellum-specific normalization known. We did not find significant correlation between paternal gray matter volume and BASCaty scores or between offspring gray matter volumes and their BASCaty scores. CONCLUSION: Expanding upon parent-of-origin effects in psychosis, maternal neuroanatomical variation was associated with daughters' PE. The nature of this sex-specific intergenerational effect is unknown, but maternally transmitted genes may relate cerebellum development to PE pathogenesis.

Effects of Palmaria palmata on lipid metabolism and glycemic control in participants with hypercholesterolemia in a randomized double-blind placebo-controlled trial.

BACKGROUND: Red algae have been reported to improve lipid and glucose metabolism in rats. We investigated the effects of Palmaria palmata (P. palmata), a red alga from northern Japan, on lipid metabolism and glycemic control in participants with hypercholesterolemia. METHODS: We conducted an 8-week, randomized, double-blind, placebo-controlled, and parallel-group comparison trial. The study enrolled Japanese participants with a serum low-density protein cholesterol (LDL-C) ≥120 mg/dL. The participants were randomly assigned to take either capsules containing P. palmata (2 g/day) or placebo capsules. The primary endpoint was the change in LDL-C from baseline to week 8 and the secondary endpoints were the changes in other lipid parameters and glycemic control. RESULTS: Of the 104 participants completed the study protocol. There were no significant differences in change in LDL-C, body mass index, waist circumference, or glycemic control between the two groups. However, serum triglyceride showed significantly greater improvement in women in the P. palmata group (-9.0 [-25.0, +5.0]) vs. those in the placebo group (-1.0 [-11.0, +19.0]; p = .03). CONCLUSIONS: The present study did not show that P. palmata had significant effect on serum LDL-C nor glycemic control, but hypertriglyceridemia could be ameliorated by administration of P. palmata in women.

Decreased electrodermal activity in patients with epilepsy.

OBJECTIVE: Biofeedback therapy using electrodermal activity (EDA) is a new noninvasive therapy for intractable epilepsy. However, the characteristics of EDA in patients with epilepsy are little known; therefore, we assessed the EDA characteristics in patients with epilepsy. METHODS: A cross-sectional observational study was conducted in 22 patients with epilepsy and 24 healthy individuals. We collected information on demographic characteristics, EDA, and state anxiety from both groups, and epilepsy diagnosis, seizure number per month, disease duration, and number of antiepileptic drugs (AED) from the epilepsy group. A wristband device was used to measure resting EDA from both wrists for 10 min under controlled temperature and humidity. We compared the EDA levels between the epilepsy group and the control group and examined correlations between EDA and epilepsy-associated factors in the epilepsy group. RESULTS: A decreasing trend in EDA was observed during the first 1 min from the start of the measurement in 22 patients with epilepsy (with or without seizures) compared with healthy controls (P = 0.12). However, a significant decrease in EDA was found in 18 patients with epilepsy with seizures compared with healthy controls (-0.48 versus -0.26; P = 0.036). Furthermore, seizure frequency showed a significant inverse correlation with EDA in the epilepsy group (ρ = -0.50, P = 0.016). However, neither disease duration nor the number of drugs prescribed correlated with EDA in the epilepsy group . SIGNIFICANCE: Marginally decreased EDA was observed in patients with epilepsy, and significantly decreased EDA was found in patients with a higher seizure frequency. The present findings shed light on the appropriateness of EDA-biofeedback therapy in epilepsy.

The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels.

Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic-pituitary-adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the "stress hormone," is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox.

Childhood parental bonding affects adulthood trait anxiety through self-esteem.

INTRODUCTION: The association between trait anxiety and parental bonding has been suggested. However, the mechanism remains uncertain and there is no study focused on general adult population. We investigated the association and the mechanism between childhood parental bonding and adulthood trait anxiety in the general adult population. MATERIAL AND METHODS: A cross-sectional retrospective survey was conducted in 2014 with 853 adult volunteers from the general population. The Parental Bonding Instrument, Rosenberg Self-Esteem Scale, and State-Trait Anxiety Inventory Form Y (STAI-Y) were self-administered. Structural equation modelling was used for the analysis. RESULTS: Childhood parental bonding affected adulthood trait anxiety indirectly mediated by self-esteem. Trait anxiety was decreased by parental care and increased by parental overprotection through self-esteem. This model explained 51.1% of the variability in STAI-Y trait anxiety scores. CONCLUSIONS: This study suggests an important role of self-esteem as a mediator between childhood parental bonding and adulthood trait anxiety.

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

AIM: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. METHODS: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. RESULTS: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

VGluT3-expressing CCK-positive basket cells construct invaginating synapses enriched with endocannabinoid signaling proteins in particular cortical and cortex-like amygdaloid regions of mouse brains.

Invaginating synapses in the basal amygdala are a unique type of GABAergic synapses equipped with molecular-anatomical organization specialized for 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling. Cholecystokinin (CCK)-positive basket cell terminals protrude into pyramidal cell somata and form invaginating synapses, where apposing presynaptic and postsynaptic elements are highly loaded with cannabinoid receptor CB1 or 2-AG synthetic enzyme diacylglycerol lipase-α (DGLα), respectively. The present study scrutinized their neurochemical and neuroanatomical phenotypes in adult mouse telencephalon. In the basal amygdala, vesicular glutamate transporter-3 (VGluT3) was transcribed in one-fourth of CB1-expressing GABAergic interneurons. The majority of VGluT3-positive CB1-expressing basket cell terminals apposed DGLα clusters, whereas the majority of VGluT3-negative ones did not. Importantly, VGluT3-positive basket cell terminals selectively constructed invaginating synapses. GABAA receptors accumulated on the postsynaptic membrane of invaginating synapses, whereas metabotropic glutamate receptor-5 (mGluR5) was widely distributed on the somatodendritic surface of pyramidal cells. Moreover, CCK2 receptor (CCK2R) was highly transcribed in pyramidal cells. In cortical regions, pyramidal cells equipped with such VGluT3/CB1/DGLα-accumulated invaginating synapses were found at variable frequencies depending on the subregions. Therefore, in addition to extreme proximity of CB1- and DGLα-loaded presynaptic and postsynaptic elements, tripartite transmitter phenotype of GABA/glutamate/CCK is the common neurochemical feature of invaginating synapses, suggesting that glutamate, CCK, or both can promote 2-AG synthesis through activating Gαq/11 protein-coupled mGluR5 and CCK2R. These molecular configurations led us to hypothesize that invaginating synapses might be evolved to provide some specific mechanisms of induction, regulation, and cooperativity for 2-AG-mediated retrograde signaling in particular cortical and cortex-like amygdaloid regions.

Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey.

AIM: Though genetic factors play a major role in the pathophysiology of psychoses including bipolar disorder (BD) and schizophrenia, lack of well-established causative genetic mutations hampers their neurobiological studies. Darier's disease, an autosomal dominant skin disorder caused by mutations of ATP2A2 on chromosome 12q23-24.1, encoding sarco/endoplasmic reticulum calcium transporting ATPase 2 (SERCA2), reportedly cosegregates with BD. A recent genome-wide association study showed an association of schizophrenia with ATP2A2. METHODS: We sequenced all coding regions of ATP2A2 in a newly identified patient with Darier's disease and BD. In addition, we performed a literature survey to examine whether likely gene disrupting (LGD) mutations are related to psychoses. RESULTS: We identified a rare heterozygous mutation, c.1288-6A>G, at the 3' end of intron 10 in the patient. A minigene splicing assay showed that this mutation introduces a new splice site causing a frameshift and premature stop codon. A literature survey of case reports of patients with Darier's disease and psychoses revealed that the rate of LGD mutations causing frameshift, altered splicing, gain of stop codon, or loss of start codon was significantly higher among the mutations harbored by these cases (9 of 11) than that of ATP2A2 mutations for which comorbidity of psychosis was not reported (107 of 237, P = 0.026). The only non-LGD mutation (p.C560R) reported in patients with Darier's disease and BD caused decreased ATP2A2 protein expression. CONCLUSION: These results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.