A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Lithium is an effective treatment for Bipolar Disorder (BD) and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania.</p> <p>Results</p> <p>Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes.</p> <p>Conclusions</p> <p>We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel hypotheses for validation in future work, we prioritized SNPs near genes in the network based on functional annotation. We also developed a "concept signature" for the genes in the network and identified additional candidate genes that may influence the system because they are significantly associated with the signature.</p

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Behavioral and synaptic circuit analysis in models of neuropsychiatric disorders: Dissecting the in vivo role of the postsynaptic density proteins nArgBP2 and Shank3 using genetic engineered mice

Dissertation presented to obtain the Ph.D degree in BiologyUnderstanding how discrete genes affect neuronal biology, synaptic function and, ultimately, behavior is a major goal in neuroscience. Not surprisingly, genes believed to be involved in human psychiatric and developmental brain disorders garner the most attention due to the likelihood that their disruption will promote salient changes in neurobiological functions. They also promise to nurture further understanding of relevant biomedical questions. Using the mouse as a model organism accelerates this discovery process because the species is amenable to manipulation at the genetic level, allowing for the orthologous recreation of human mutations. Simultaneously, our understanding of murine behavioral outputs can now be linked to particular endophenotypes reminiscent of human disorders.(...)Apoio financeiro da FCT e do FSE no âmbito do Quadro Comunitário de Apoio (SFRH/BD/15855-2005

Purinergic Signalling and Neurological Diseases: An Update

Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer’s, Parkinson’s and Huntington’s diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson’s disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders

Differential regulation of synaptic plasticity, mood and reward behavior by circadian genes

Endogenously generated circadian rhythms allow living organisms to entrain to photic and non- photic cues in a changing environment. The master pacemaker region, the suprachiasmatic nucleus (SCN) coordinates the activity of several sub-oscillators throughout the brain and periphery to produce daily variation in physiology and activity patterns. However, SCN-autonomous rhythms also exist in mesocorticolimbic brain regions. The disruption of these rhythms at the molecular level can have dire consequences for physical and mental health. Clinical and preclinical studies provide a strong link between circadian gene perturbations and the development and progression of mood and substance abuse disorders including bipolar disorder (BD) and co-morbid addiction. While much is known about the inner workings of the SCN clock, the specific underlying mechanisms governing the regulation of mood and reward-related behavior by extra-SCN clock proteins are yet to be fully elucidated. Molecular rhythms are maintained by transcription factors, CLOCK and NPAS2, which are homologous in structure and function but differentially expressed throughout the brain. Genetic variants of both have been found to associate with neuropsychiatric illnesses in human populations. The expression profiles and uniquely regulated gene targets of these proteins however, may contribute to differences in their ability to modulate behavior. The work presented here focuses on how disruptions in CLOCK and NPAS2 alter mesolimbic excitatory neurotransmission and their effects on mood and reward-related behavior. We find that a mutation in CLOCK, which produces a dominant negative protein, and a behavioral phenotype in mice closely resembling human mania, leads to a reduction in excitatory neurotransmission in the nucleus accumbens (NAc) a region critical for sensorimotor and limbic integration. These mice have also been characterized to be hyperhedonic with increased reward sensitivity. In contrast, a disruption in NPAS2 by viral- mediated knockdown, increases NAc excitatory synaptic transmission and incidentally decreases reward sensitivity in a cell-type specific manner. Electrophysiological, molecular, biochemical and behavioral studies contained within this dissertation aim to uncover the differential regulation of behavior by these core circadian proteins. The understanding of these mechanisms may help to inform targeted therapeutic strategies against BD and other disorders for which there is a strong circadian component

Molecular Brain Adaptations to Ethanol: Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption

Alcoholism is a complex neuropsychiatric disease that is characterized by compulsive alcohol use and intensifying cravings and withdrawals, often culminating in physiologic dependency. Fundamental alterations in brain chemistry underlie the transition from initial ethanol exposure to repetitive excessive use. Key mediators of this adaptation include changes in gene expression and signal transduction. Here we investigated gene expression pathways in prefrontal cortex and nucleus accumbens following acute or chronic ethanol treatment, to identify genes with potentially conserved involvement in the long-term response of the corticolimbic system to repeated ethanol exposure. We investigated Gsk3b, which encodes glycogen synthase kinase 3-beta, as a highly ethanol responsive gene associated with risk for long-term maladaptive responses to ethanol. On the level of the protein, we found that GSK3B and to a lesser extent the GSK3A isoform showed robust increases in inhibitory phosphorylation following acute ethanol. This inhibition may underlie aspects of the behavioral response to acute ethanol, as pre-treatment with a GSK3B inhibitor (tideglusib) augmented ethanol’s locomotor effects. Following long term ethanol exposure, we re-tested GSK3B phosphorylation and found that its ethanol response is blunted, consistent with molecular tolerance as a corollary to increased consumption. As the prefrontal cortex (PFC) plays a vital role in the reward pathway via its glutamatergic projections to the nucleus accumbens, we investigated the role of the Gsk3b gene specifically in PFC and in glutamatergic neurons. Overexpression of Gsk3b in the PFC robustly increased ethanol consumption, while deletion in Camk2a-positive neurons significantly attenuated ethanol consumption. Pharmacologic antagonism of GSK3B also decreased drinking in a model of binge-like consumption. Collectively this data implicates GSK3B as a mediator of excessive ethanol intake via its kinase activity, wherein inhibition of the kinase via phosphorylation exerts a protective effect in the context of acute ethanol, but desensitizes with repeated exposure

Timing matters: Using optogenetics to chronically manipulate neural circuitry and rhythms

The ability to probe defined neural circuits with both the spatial and temporal resolution imparted by optogenetics has transformed the field of neuroscience. Although much attention has been paid to the advantages of manipulating neural activity at millisecond timescales in order to elicit time-locked neural responses, little consideration has been given to the manipulation of circuit activity at physiologically relevant times of day, across multiple days. Nearly all biological events are governed by the circadian clock and exhibit 24 h rhythms in activity. Indeed, neural circuit activity itself exhibits a daily rhythm with distinct temporal peaks in activity occurring at specific times of the day. Therefore, experimentally probing circuit function within and across physiologically relevant time windows (minutes to hours) in behaving animals is fundamental to understanding the function of any one particular circuit within the intact brain. Furthermore, understanding how circuit function changes with repeated manipulation is important for modeling the circuit-wide disruptions that occur with chronic disease states. Here, we review recent advances in optogenetic technology that allow for chronic, temporally specific, control of circuit activity and provide examples of chronic optogenetic paradigms that have been utilized in the search for the neural circuit basis of behaviors relevant to human neuropsychiatric disease. © 2014 Sidor and McClung

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.Felicity Ng, Michael Berk, Olivia Dean and Ashley I. Bus