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Molecular Psychiatry

Toby Pillinger, Enrico D'Ambrosio, Robert McCutcheon, Oliver D Howes
People with psychotic disorders show abnormalities in several organ systems in addition to the central nervous system (CNS); and this contributes to excess mortality. However, it is unclear how strong the evidence is for alterations in non-CNS systems at the onset of psychosis, how the alterations in non-CNS systems compare to those in the CNS, or how they relate to symptoms. Here, we consider these questions, and suggest potential models to account for findings. We conducted a systematic meta-review to summarize effect sizes for both CNS (focusing on brain structural, neurophysiological, and neurochemical parameters) and non-CNS dysfunction (focusing on immune, cardiometabolic, and hypothalamic-pituitary-adrenal (HPA) systems) in first-episode psychosis (FEP)...
May 9, 2018: Molecular Psychiatry
Massimo Filippi, Silvia Basaia, Elisa Canu, Francesca Imperiale, Giuseppe Magnani, Monica Falautano, Giancarlo Comi, Andrea Falini, Federica Agosta
The aim of this study was two-fold: (i) to investigate structural and functional brain network architecture in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), stratified in converters (c-aMCI) and non-converters (nc-aMCI) to AD; and to assess the relationship between healthy brain network functional connectivity and the topography of brain atrophy in patients along the AD continuum. Ninety-four AD patients, 47 aMCI patients (25 c-aMCI within 36 months) and 53 age- and sex-matched healthy controls were studied...
May 9, 2018: Molecular Psychiatry
Carine Thalman, Guilherme Horta, Lianyong Qiao, Heiko Endle, Irmgard Tegeder, Hong Cheng, Gregor Laube, Torfi Sigrudsson, Maria Jelena Hauser, Stefan Tenzer, Ute Distler, Junken Aoki, Andrew J Morris, Gerd Geisslinger, Jochen Röper, Sergei Kirischuk, Heiko J Luhmann, Konstantin Radyushkin, Robert Nitsch, Johannes Vogt
Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses...
May 9, 2018: Molecular Psychiatry
Euripedes C Miguel, Antonio C Lopes, Nicole C R McLaughlin, Georg Norén, André F Gentil, Clement Hamani, Roseli G Shavitt, Marcelo C Batistuzzo, Edoardo F Q Vattimo, Miguel Canteras, Antonio De Salles, Alessandra Gorgulho, João Victor Salvajoli, Erich Talamoni Fonoff, Ian Paddick, Marcelo Q Hoexter, Christer Lindquist, Suzanne N Haber, Benjamin D Greenberg, Sameer A Sheth
For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions...
May 9, 2018: Molecular Psychiatry
Mads E Hauberg, John F Fullard, Lingxue Zhu, Ariella T Cohain, Claudia Giambartolomei, Ruth Misir, Sarah Reach, Jessica S Johnson, Minghui Wang, Manuel Mattheisen, Anders Dupont Børglum, Bin Zhang, Solveig K Sieberts, Mette A Peters, Enrico Domenici, Eric E Schadt, Bernie Devlin, Pamela Sklar, Kathryn Roeder, Panos Roussos
Transcription at enhancers is a widespread phenomenon which produces so-called enhancer RNA (eRNA) and occurs in an activity-dependent manner. However, the role of eRNA and its utility in exploring disease-associated changes in enhancer function, and the downstream coding transcripts that they regulate, is not well established. We used transcriptomic and epigenomic data to interrogate the relationship of eRNA transcription to disease status and how genetic variants alter enhancer transcriptional activity in the human brain...
May 8, 2018: Molecular Psychiatry
Suzanna G M Frints, Aysegul Ozanturk, Germán Rodríguez Criado, Ute Grasshoff, Bas de Hoon, Michael Field, Sylvie Manouvrier-Hanu, Scott E Hickey, Molka Kammoun, Karen W Gripp, Claudia Bauer, Christopher Schroeder, Annick Toutain, Theresa Mihalic Mosher, Benjamin J Kelly, Peter White, Andreas Dufke, Eveline Rentmeester, Sungjin Moon, Daniel C Koboldt, Kees E P van Roozendaal, Hao Hu, Stefan A Haas, Hans-Hilger Ropers, Lucinda Murray, Eric Haan, Marie Shaw, Renee Carroll, Kathryn Friend, Jan Liebelt, Lynne Hobson, Marjan De Rademaeker, Joep Geraedts, Jean-Pierre Fryns, Joris Vermeesch, Martine Raynaud, Olaf Riess, Joost Gribnau, Nicholas Katsanis, Koen Devriendt, Peter Bauer, Jozef Gecz, Christelle Golzio, Cristina Gontan, Vera M Kalscheuer
RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations...
May 4, 2018: Molecular Psychiatry
Mary R Lee, Jenica D Tapocik, Mwlod Ghareeb, Melanie L Schwandt, Alexandra A Dias, April N Le, Enoch Cobbina, Lisa A Farinelli, Sofia Bouhlal, Mehdi Farokhnia, Markus Heilig, Fatemeh Akhlaghi, Lorenzo Leggio
Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats...
May 4, 2018: Molecular Psychiatry
Ryan W Logan, Puja K Parekh, Gabrielle N Kaplan, Darius D Becker-Krail, Wilbur P Williams, Shintaro Yamaguchi, Jun Yoshino, Micah A Shelton, Xiyu Zhu, Hui Zhang, Spencer Waplinger, Ethan Fitzgerald, Jeffrey Oliver-Smith, Poornima Sundarvelu, John F Enwright, Yanhua H Huang, Colleen A McClung
The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration...
May 4, 2018: Molecular Psychiatry
Antonio Di Meco, Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy...
May 4, 2018: Molecular Psychiatry
Olivier Nicole, Donald M Bell, Thierry Leste-Lasserre, Hélène Doat, François Guillemot, Emilie Pacary
Perturbation of CaMKIIβ expression has been associated with multiple neuropsychiatric diseases, highlighting CaMKIIβ as a gene of interest. Yet, in contrast to CaMKIIα, the specific functions of CaMKIIβ in the brain remain poorly explored. Here, we reveal a novel function for this CaMKII isoform in vivo during neuronal development. By using in utero electroporation, we show that CaMKIIβ is an important regulator of radial migration of projection neurons during cerebral cortex development. Knockdown of CaMKIIβ causes accelerated migration of nascent pyramidal neurons, whereas overexpression of CaMKIIβ inhibits migration, demonstrating that precise regulation of CaMKIIβ expression is required for correct neuronal migration...
April 30, 2018: Molecular Psychiatry
Francesco Bartoli, Massimo Clerici, Giuseppe Carrà
No abstract text is available yet for this article.
April 30, 2018: Molecular Psychiatry
Michele Ferrante, A David Redish, Maria A Oquendo, Bruno B Averbeck, Megan E Kinnane, Joshua A Gordon
No abstract text is available yet for this article.
April 27, 2018: Molecular Psychiatry
Philippe Jawinski, Holger Kirsten, Christian Sander, Janek Spada, Christine Ulke, Jue Huang, Ralph Burkhardt, Markus Scholz, Tilman Hensch, Ulrich Hegerl
Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort...
April 27, 2018: Molecular Psychiatry
Fuchen Liu, Yun Zhang, Zonglai Liang, Qianwen Sun, Heng Liu, Juan Zhao, Jingwen Xu, Jinfan Zheng, Yan Yun, Xiao Yu, Weihong Song, Xiulian Sun
Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Aβ, a central component of neuritic plaques in Alzheimer's brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2...
April 27, 2018: Molecular Psychiatry
Qionger He, Erica D Arroyo, Samuel N Smukowski, Jian Xu, Claire Piochon, Jeffrey N Savas, Carlos Portera-Cailliau, Anis Contractor
Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP...
April 27, 2018: Molecular Psychiatry
Sarah M Williams, Joon Yong An, Janette Edson, Michelle Watts, Valentine Murigneux, Andrew J O Whitehouse, Colin J Jackson, Mark A Bellgrove, Alexandre S Cristino, Charles Claudianos
A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants...
April 27, 2018: Molecular Psychiatry
Kimberly H LeBlanc, Tanisha D London, Ilona Szczot, Miriam E Bocarsly, Danielle M Friend, Katrina P Nguyen, Marda M Mengesha, Marcelo Rubinstein, Veronica A Alvarez, Alexxai V Kravitz
The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement...
April 25, 2018: Molecular Psychiatry
Arthur Caye, Ives C Passos, Mauricio Kunz, Marcia Kauer-Sant'anna
No abstract text is available yet for this article.
April 24, 2018: Molecular Psychiatry
Xinyu Zhou, Lanxiang Liu, Xinghui Lan, David Cohen, Yuqing Zhang, Arun V Ravindran, Shuai Yuan, Peng Zheng, David Coghill, Lining Yang, Sarah E Hetrick, Xiaofeng Jiang, Jean-Jacques Benoliel, Andrea Cipriani, Peng Xie
Major depressive disorder (MDD) in children and adolescents is a recurrent and disabling condition globally but its pathophysiology remains poorly elucidated and there are limited effective treatments available. We performed metabolic profiling of plasma samples based on ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry to explore the potential biomarkers of depression in children and adolescents with MDD. We identified several perturbed pathways, including fatty acid metabolism-particularly the polyunsaturated fatty acids metabolism, and purine metabolism-that were associated with MDD in these young patients...
April 20, 2018: Molecular Psychiatry
Sameer Jauhar, Mattia Veronese, Matthew M Nour, Maria Rogdaki, Pamela Hathway, Federico E Turkheimer, James Stone, Alice Egerton, Philip McGuire, Shitij Kapur, Oliver D Howes
Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in non-responders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18 F-DOPA Positron Emission Tomography scan to measure DSC (Kicer ) prior to antipsychotic treatment...
April 20, 2018: Molecular Psychiatry
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