Amit Lotan

Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.

Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders—attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10−5). 22% of genes overlapped two or more disorders. The most widely shared subset of genes—common to five of six disorders–included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20–30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.

Neurotransmitters and electroconvulsive therapy.

Objectives Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatment-refractory depression. However, despite ECT’s widespread use, the exact neurobiological mechanisms underlying its efficacy are not fully understood. Over the past 3 decades, extensive work in rodents, primates, and humans has begun to delineate the impact of electroconvulsive seizures (ECS) and ECT on neurotransmission systems commonly implicated in depression. In the current review, we will focus on two major biogenic amine systems, namely serotonin and dopamine. Methods The database of PubMed was searched for preclinical studies describing the effects of ECS on the serotonergic and dopaminergic system using behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA and protein expression, electrophysiology, and positron emission tomography. Additionally, human data describing ECT’s effects on neurotransmitter turnover, receptor binding, and functional imaging were reviewed together with relevant genetic association studies. Results Literature research resulted in 40 published original studies related to ECS/ECT and the serotonergic system, whereby only three were studies in humans. Regarding dopamine, 15 preclinical and 12 human studies were found in PubMed database. Conclusions Converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier preclinical and clinical findings relating to enhancement of serotonergic neurotransmission and activation of the mesocorticolimbic dopamine system after ECS/ECT. Moreover, it seems that these effects are evident at various levels, including neurotransmitter release, receptor binding, and overall neurotransmission. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT’s profound antidepressant effect and would support the development of better pharmacological and somatic treatment approaches for refractory depression.

Differential Impact of Selective Serotonin Reuptake Inhibitors on Platelet Response to Clopidogrel: A Randomized, Double‐Blind, Crossover Trial

To assess the effect of two selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and citalopram, that markedly differ in their level of cytochrome P450 (CYP) 2C19 inhibition, on the laboratory response to clopidogrel, a prodrug requiring metabolism by the CYP system, and especially CYP2C19, to produce its active form.

Anti-NMDA Receptor Encephalitis Presenting as an Acute Psychotic Episode in a Young Woman: An Underdiagnosed yet Treatable Disorder

Anti-NMDA receptor (NMDAR) encephalitis is a recently identified autoimmune disorder with prominent psychiatric symptoms. Patients usually present with acute behavioral change, psychosis, catatonic symptoms, memory deficits, seizures, dyskinesias, and autonomic instability. In female patients an ovarian teratoma is often identified. We describe a 32-year-old woman who presented with acute psychosis. Shortly after admission, she developed generalized seizures and deteriorated into a catatonic state. Although ancillary tests including MRI, electroencephalogram, and cerebrospinal fluid (CSF) analysis were unremarkable, the presentation of acute psychosis in combination with recurrent seizures and a relentless course suggested autoimmune encephalitis. The patient underwent pelvic ultrasound which disclosed a dermoid cyst and which led to an urgent cystectomy. Plasmapheresis was then initiated, yielding partial response over the next two weeks. Following the detection of high titers of anti-NMDAR antibodies in the CSF, the patient ultimately received second line immunosuppressive treatment with rituximab. Over several months of cognitive rehabilitation a profound improvement was eventually noted, although minor anterograde memory deficits remained. In this report we call for attention to the inclusion of anti-NMDAR encephalitis in the differential diagnosis of acute psychosis. Prompt diagnosis is critical as early immunotherapy and tumor removal could dramatically affect outcomes.

Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes.

Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

The Abelson helper integration site 1 (Ahi1) gene plays a pivotal role in brain development and is associated with genetic susceptibility to schizophrenia, and other neuropsychiatric disorders. Translational research in genetically modified mice may reveal the neurobiological mechanisms of such associations. Previous studies of mice heterozygous for Ahi1 knockout (Ahi1+/−) revealed an attenuated anxiety response on various relevant paradigms, in the context of a normal glucocorticoid response to caffeine and pentylenetetrazole. Resting-state fMRI showed decreased amygdalar connectivity with various limbic brain regions and altered network topology. However, it was not clear from previous studies whether stress-hyporesponsiveness reflected resilience or, conversely, a cognitive-emotional deficit. The present studies were designed to investigate the response of Ahi1+/− mice to chronic unpredictable stress (CUS) applied over 9 weeks. Wild type (Ahi1+/+) mice were significantly affected by CUS, manifesting decreased sucrose preference (p < 0.05); reduced anxiety on the elevated plus maze and light dark box and decreased thigmotaxis in the open field (p < 0.01 0.05); decreased hyperthermic response to acute stress (p < 0.05); attenuated contextual fear conditioning (p < 0.01) and increased neurogenesis (p < 0.05). In contrast, Ahi1+/− mice were indifferent to the effects of CUS assessed with the same parameters. Our findings suggest that Ahi1 under-expression during neurodevelopment, as manifested by Ahi1+/− mice, renders these mice stress hyporesponsive. Ahi1 deficiency during development may attenuate the perception and/or integration of environmental stressors as a result of impaired corticolimbic connectivity or aberrant functional wiring. These neural mechanisms may provide initial clues as to the role Ahi1 in schizophrenia and other neuropsychiatric disorders.

Methylphenidate facilitates hypnotizability in adults with ADHD: a naturalistic cohort study.

Abstract Impaired attention may impede learning of adaptive skills in ADHD. While manipulations that reduce competition between attentional processes, including hypnosis, could boost learning, their feasibility in ADHD is unknown. Because hypnotic phenomena rely on attentional mechanisms, the authors aimed to assess whether stimulants could enhance hypnotizability in ADHD. In the current study, stimulant-naïve patients seeking treatment for ADHD-related symptoms were assessed with the Stanford Hypnotic Susceptibility Scale (SHSS) at baseline and during methylphenidate treatment. Methylphenidate dose and SHSS increase were negatively correlated with baseline SHSS scores. Upon reaching effective doses, mean SHSS scores increased significantly. All patients who had been poorly hypnotizable at baseline demonstrated moderate-to-high hypnotizability at follow-up. The data support methylphenidate enhancement of hypnotizability in ADHD, thus highlighting novel treatment approaches for this disabling disorder.

The Effect of Chronic Stress on Weight And Hypothalamic Insulin And Melanocortin 4 Receptors In Young And old Female Mice

Background Chronic stress (CS) has a deleterious effect on several physiological systems, among them cognition, memory and the regulation of appetite and weight. In humans, stress can cause weight gain in some people, but weight loss in others. Weight loss, mainly in advanced ages, is a major health concern. The exact mechanism is unknown; however, chronic psychological and social stressors are considered among the main contributing factors. The central site for appetite regulation is located in the hypothalamus. Insulin enters the central nervous system (CNS) in proportion to its plasma level and start a cascade that controls food intake. Activation of Melanocortin 4 receptors (MC4R) on neurons in the paraventricular hypothalamic nucleus (PVN), decreases food intake while elevating energy utilization The present study was designed to gain a mechanistic understanding of the age-related effects of chronic stress on weight and to try to explore for the mechanisms of weight change in the context of chronic stress in mice. Methods 62 female C57BL/6JRccHsd mice aged 3 months (young) and 20-23 months (old) were used in this study . Mice were housed in groups of 4-5 . Food and water were provided ad libitum. Old and young mice were divided into equally sized subgroups that underwent a chronic stress (CS) regimen or were maintained under regular animal facility conditions (Control). Mice were weighed once weekly. Mice were sacrificed, hypothalami were dissected and mRNA was extracted. To measure the expression of IR and MC4R, real time PCR (rtPCR) was used. Results Old mice were more vulnerable to the effects of chronic stress on weight than young mice. Two way ANOVA with repeated measures comparing changes in body weight from baseline (i.e. before onset of stress protocol) until after eight concessive weeks of CS revealed a significant age by time interaction (F [2,58] = 11.126, p=0. 009). Ins-R expression in the hypothalamus was quantified by rtPCR in young vs. very old female mice subject to CS or control conditions. A 2-way ANOVA with age and treatment as independent variables yielded a significant main effect of treatment (F[1,18]=5, p=0.038). MC4R expression in the hypothalamus was quantified by rtPCR in young vs. very old female mice subjected to CS or control conditions. A 2-way ANOVA with age and treatment as independent variables yielded a strong, highly-significant main effect of age (F[1,23]=23.4, p Discussion In the present study, we compared four groups of female mice: young and old control mice versus young and old mice in CS conditions. We found that female mice lost weight under CS conditions significantly more than the rest of the groups. We hypothesized that a change in the mRNA expression of Ins-R and MC4R, will indicate for the mechanism of weight loss in that group. The results indicate that there is an increase in hypothalamic Ins-R expression under CS without regard to age. This result in itself is novel and in view of the paucity of knowledge that exists regarding the role of insulin in the CNS. The expression of MC4R did not show any significant interaction with CS exposure, but there was a significant rise in expression in old mice versus young mice. This may imply that in old age, CRH neurons in the PVN are more sensitive to anorexigenic signals than in young age.