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Molecular Psychiatry

Adam K Walker, Emily E Wing, William A Banks, Robert Dantzer
Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depression-like behavior, mice were treated with lipopolysaccharide (LPS, 0...
July 9, 2018: Molecular Psychiatry
Fengjiao Sun, Yun Lei, Jingjing You, Chen Li, Linshan Sun, Jacob Garza, Di Zhang, Ming Guo, Phillip E Scherer, Daniel Lodge, Xin-Yun Lu
Adiponectin, a metabolic hormone secreted by adipocytes, can cross the blood-brain barrier to act on neurons in different brain regions, including those involved in stress-related disorders. Here we show that dopamine neurons in the ventral tegmental area (VTA) express adiponectin receptor 1 (AdipoR1). Intra-VTA infusion of adiponectin or the adiponectin mimetic AdipoRon in wild-type mice decreases basal dopamine neuron population activity and firing rate and reverses the restraint stress-induced increase in dopamine neuron activity and anxiety behavior...
July 9, 2018: Molecular Psychiatry
Jordi Merino, Hassan S Dashti, Sherly X Li, Chloé Sarnowski, Anne E Justice, Misa Graff, Constantina Papoutsakis, Caren E Smith, George V Dedoussis, Rozenn N Lemaitre, Mary K Wojczynski, Satu Männistö, Julius S Ngwa, Minjung Kho, Tarunveer S Ahluwalia, Natalia Pervjakova, Denise K Houston, Claude Bouchard, Tao Huang, Marju Orho-Melander, Alexis C Frazier-Wood, Dennis O Mook-Kanamori, Louis Pérusse, Craig E Pennell, Paul S de Vries, Trudy Voortman, Olivia Li, Stavroula Kanoni, Lynda M Rose, Terho Lehtimäki, Jing Hua Zhao, Mary F Feitosa, Jian'an Luan, Nicola M McKeown, Jennifer A Smith, Torben Hansen, Niina Eklund, Mike A Nalls, Tuomo Rankinen, Jinyan Huang, Dena G Hernandez, Christina-Alexandra Schulz, Ani Manichaikul, Ruifang Li-Gao, Marie-Claude Vohl, Carol A Wang, Frank J A van Rooij, Jean Shin, Ioanna P Kalafati, Felix Day, Paul M Ridker, Mika Kähönen, David S Siscovick, Claudia Langenberg, Wei Zhao, Arne Astrup, Paul Knekt, Melissa Garcia, D C Rao, Qibin Qi, Luigi Ferrucci, Ulrika Ericson, John Blangero, Albert Hofman, Zdenka Pausova, Vera Mikkilä, Nick J Wareham, Sharon L R Kardia, Oluf Pedersen, Antti Jula, Joanne E Curran, M Carola Zillikens, Jorma S Viikari, Nita G Forouhi, José M Ordovás, John C Lieske, Harri Rissanen, André G Uitterlinden, Olli T Raitakari, Jessica C Kiefte-de Jong, Josée Dupuis, Jerome I Rotter, Kari E North, Robert A Scott, Michael A Province, Markus Perola, L Adrienne Cupples, Stephen T Turner, Thorkild I A Sørensen, Veikko Salomaa, Yongmei Liu, Yun J Sung, Lu Qi, Stefania Bandinelli, Stephen S Rich, Renée de Mutsert, Angelo Tremblay, Wendy H Oddy, Oscar H Franco, Tomas Paus, Jose C Florez, Panos Deloukas, Leo-Pekka Lyytikäinen, Daniel I Chasman, Audrey Y Chu, Toshiko Tanaka
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6 ) associated with intake of any macronutrient in 91,114 European ancestry participants...
July 9, 2018: Molecular Psychiatry
Haitham Amal, Boaz Barak, Vadiraja Bhat, Guanyu Gong, Brian A Joughin, John S Wishnok, Guoping Feng, Steven R Tannenbaum
Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO• )-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions...
July 9, 2018: Molecular Psychiatry
Daniela Hartl, Patrick May, Wei Gu, Manuel Mayhaus, Sabrina Pichler, Christian Spaniol, Enrico Glaab, Dheeraj Reddy Bobbili, Paul Antony, Sandra Koegelsberger, Alexander Kurz, Timo Grimmer, Kevin Morgan, Badri N Vardarajan, Christiane Reitz, John Hardy, Jose Bras, Rita Guerreiro, Rudi Balling, Jochen G Schneider, Matthias Riemenschneider
Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family...
July 9, 2018: Molecular Psychiatry
Hidenori Yamasue, Takashi Okada, Toshio Munesue, Miho Kuroda, Toru Fujioka, Yota Uno, Kaori Matsumoto, Hitoshi Kuwabara, Daisuke Mori, Yuko Okamoto, Yuko Yoshimura, Yuki Kawakubo, Yuko Arioka, Masaki Kojima, Teruko Yuhi, Keiho Owada, Walid Yassin, Itaru Kushima, Seico Benner, Nanayo Ogawa, Yosuke Eriguchi, Naoko Kawano, Yukari Uemura, Maeri Yamamoto, Yukiko Kano, Kiyoto Kasai, Haruhiro Higashida, Norio Ozaki, Hirotaka Kosaka
Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8...
June 29, 2018: Molecular Psychiatry
Michael Michaelides, Michael L Miller, Gabor Egervari, Stefany D Primeaux, Juan L Gomez, Randall J Ellis, Joseph A Landry, Henrietta Szutorisz, Alexander F Hoffman, Carl R Lupica, Ruth J F Loos, Panayotis K Thanos, George A Bray, John F Neumaier, Venetia Zachariou, Gene-Jack Wang, Nora D Volkow, Yasmin L Hurd
Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role...
June 28, 2018: Molecular Psychiatry
Arthur Caye, James M Swanson, David Coghill, Luis Augusto Rohde
Attention-deficit/hyperactivity disorder (ADHD) is a common and impairing disorder affecting children, adolescents, and adults. Several treatment strategies are available that can successfully ameliorate symptoms, ranging from pharmacological to dietary interventions. Due to the increasing range of available options, an informed selection or prioritization of treatments is becoming harder for clinicians. This review aims to provide an evidence-based appraisal of the literature on ADHD treatment, supplemented by expert opinion on plausibility...
June 28, 2018: Molecular Psychiatry
David C Glahn, Vishwajit L Nimgaonkar, Henriette Raventós, Javier Contreras, Andrew M McIntosh, Pippa A Thomson, Assen Jablensky, Nina S McCarthy, Jac C Charlesworth, Nicholas B Blackburn, Juan Manuel Peralta, Emma E M Knowles, Samuel R Mathias, Seth A Ament, Francis J McMahon, Ruben C Gur, Maja Bucan, Joanne E Curran, Laura Almasy, Raquel E Gur, John Blangero
As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness...
June 28, 2018: Molecular Psychiatry
Karen L Jones, Michael C Pride, Elizabeth Edmiston, Mu Yang, Jill L Silverman, Jacqueline N Crawley, Judy Van de Water
Immune dysregulation has been noted consistently in individuals with autism spectrum disorder (ASD) and their families, including the presence of autoantibodies reactive to fetal brain proteins in nearly a quarter of mothers of children with ASD versus <1% in mothers of typically developing children. Our lab recently identified the peptide epitope sequences on seven antigenic proteins targeted by these maternal autoantibodies. Through immunization with these peptide epitopes, we have successfully created an endogenous, antigen-driven mouse model that ensures a constant exposure to the salient autoantibodies throughout gestation in C57BL/6J mice...
June 28, 2018: Molecular Psychiatry
Gabor Egervari, Alexey Kozlenkov, Stella Dracheva, Yasmin L Hurd
Delineating the pathophysiology of psychiatric disorders has been extremely challenging but technological advances in recent decades have facilitated a deeper interrogation of molecular processes in the human brain. Initial candidate gene expression studies of the postmortem brain have evolved into genome wide profiling of the transcriptome and the epigenome, a critical regulator of gene expression. Here, we review the potential and challenges of direct molecular characterization of the postmortem human brain, and provide a brief overview of recent transcriptional and epigenetic studies with respect to neuropsychiatric disorders...
June 28, 2018: Molecular Psychiatry
Marta Peciña, Jordan F Karp, Sanjay Mathew, Mark S Todtenkopf, Elliot W Ehrich, Jon-Kar Zubieta
The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders...
June 28, 2018: Molecular Psychiatry
Mariana Temido-Ferreira, Diana G Ferreira, Vânia L Batalha, Inês Marques-Morgado, Joana E Coelho, Pedro Pereira, Rui Gomes, Andreia Pinto, Sara Carvalho, Paula M Canas, Laetitia Cuvelier, Valerie Buée-Scherrer, Emilie Faivre, Younis Baqi, Christa E Müller, José Pimentel, Serge N Schiffmann, Luc Buée, Michael Bader, Tiago F Outeiro, David Blum, Rodrigo A Cunha, Hélène Marie, Paula A Pousinha, Luísa V Lopes
Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2A R) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2A R in age-related conditions. We report, for the first time, a significant overexpression of A2A R in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2A R overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift...
June 27, 2018: Molecular Psychiatry
Samuel Turton, James Fm Myers, Inge Mick, Alessandro Colasanti, Ashwin Venkataraman, Claire Durant, Adam Waldman, Alan Brailsford, Mark C Parkin, Gemma Dawe, Eugenii A Rabiner, Roger N Gunn, Stafford L Lightman, David J Nutt, Anne Lingford-Hughes
Addiction has been proposed as a 'reward deficient' state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse...
June 25, 2018: Molecular Psychiatry
Tanya Horwitz, Katie Lam, Yu Chen, Yan Xia, Chunyu Liu
After more than 10 years of accumulated efforts, genome-wide association studies (GWAS) have led to many findings, most of which have been deposited into the GWAS Catalog. Between GWAS's inception and March 2017, the GWAS Catalog has collected 2429 studies, 1818 phenotypes, and 28,462 associated SNPs. We reclassified the psychology-related phenotypes into 217 reclassified phenotypes, which accounted for 514 studies and 7052 SNPs. In total, 1223 of the SNPs reached genome-wide significance. Of these, 147 were replicated for the same psychological trait in different studies...
June 25, 2018: Molecular Psychiatry
Jun Ma, Yan-Ping Bao, Ru-Jia Wang, Meng-Fan Su, Mo-Xuan Liu, Jin-Qiao Li, Louisa Degenhardt, Michael Farrell, Frederic C Blow, Mark Ilgen, Jie Shi, Lin Lu
Opioid use disorder (OUD) is associated with a high risk of premature death. Medication-assisted treatment (MAT) is the primary treatment for opioid dependence. We comprehensively assessed the effects of different MAT-related characteristics on mortality among those with OUD by a systematic review and meta-analysis. The all-cause and overdose crude mortality rates (CMRs) and relative risks (RRs) by treatment status, different type, period, and dose of medication, and retention time were pooled using random effects, subgroup analysis, and meta-regression...
June 22, 2018: Molecular Psychiatry
Jyothika Kumar, Elizabeth B Liddle, Carolina C Fernandes, Lena Palaniyappan, Emma L Hall, Siân E Robson, Molly Simmonite, Jan Fiesal, Mohammad Z Katshu, Ayaz Qureshi, Michael Skelton, Nikolaos G Christodoulou, Matthew J Brookes, Peter G Morris, Peter F Liddle
In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments...
June 22, 2018: Molecular Psychiatry
Karen L Jones, Judy Van de Water
It has been estimated that autism spectrum disorder (ASD) now affects 1 in 59 children in the United States. Although the cause(s) of ASD remain largely unknown, it is becoming increasingly apparent that ASD can no longer be defined simply as a behavioral disorder, but is in effect a rather complex and highly heterogeneous biological disorder. Up until recently the brain was thought to be "immune privileged." However, it is now known that the immune system plays critical roles in the development and functioning of the brain throughout life...
June 22, 2018: Molecular Psychiatry
Elodie Martin, Majid Amar, Carine Dalle, Ihsen Youssef, Céline Boucher, Caroline Le Duigou, Matthias Brückner, Annick Prigent, Véronique Sazdovitch, Annett Halle, Jean M Kanellopoulos, Bertrand Fontaine, Benoît Delatour, Cécile Delarasse
Extracellular aggregates of amyloid β (Aβ) peptides, which are characteristic of Alzheimer's disease (AD), act as an essential trigger for glial cell activation and the release of ATP, leading to the stimulation of purinergic receptors, especially the P2X7 receptor (P2X7R). However, the involvement of P2X7R in the development of AD is still ill-defined regarding the dual properties of this receptor. Particularly, P2X7R activates the NLRP3 inflammasome leading to the release of the pro-inflammatory cytokine, IL-1β; however, P2X7R also induces cleavage of the amyloid precursor protein generating Aβ peptides or the neuroprotective fragment sAPPα...
June 22, 2018: Molecular Psychiatry
Isabell Brikell, Henrik Larsson, Yi Lu, Erik Pettersson, Qi Chen, Ralf Kuja-Halkola, Robert Karlsson, Benjamin B Lahey, Paul Lichtenstein, Joanna Martin
Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology...
June 22, 2018: Molecular Psychiatry
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