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Genetic psychiatry

J Xu, B J Hartley, P Kurup, A Phillips, A Topol, M Xu, C Ononenyi, E Foscue, S-M Ho, T D Baguley, N Carty, C S Barros, U Müller, S Gupta, P Gochman, J Rapoport, J A Ellman, C Pittenger, B Aronow, A C Nairn, M W Nestor, P J Lombroso, K J Brennand
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1(+/-) knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1(+/-) mice...
October 18, 2016: Molecular Psychiatry
B Zhang, E Seigneur, P Wei, O Gokce, J Morgan, T C Südhof
Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission...
October 11, 2016: Molecular Psychiatry
L I Schmitt, M M Halassa
While localizing sensory and motor deficits is one of the cornerstones of clinical neurology, behavioral and cognitive deficits in psychiatry remain impervious to this approach. In psychiatry, major challenges include the relative subtlety by which neural circuits are perturbed, and the limited understanding of how basic circuit functions relate to thought and behavior. Neurodevelopmental disorders offer a window to addressing the first challenge given their strong genetic underpinnings, which can be linked to biological mechanisms...
October 11, 2016: Molecular Psychiatry
P H Lee, J T Baker, A J Holmes, N Jahanshad, T Ge, J-Y Jung, Y Cruz, D S Manoach, D P Hibar, J Faskowitz, K L McMahon, G I de Zubicaray, N H Martin, M J Wright, D Öngür, R Buckner, J Roffman, P M Thompson, J W Smoller
Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals...
October 11, 2016: Molecular Psychiatry
Annette Milnik, Christian Vogler, Philippe Demougin, Tobias Egli, Virginie Freytag, Francina Hartmann, Angela Heck, Fabian Peter, Klara Spalek, Attila Stetak, Dominique J-F de Quervain, Andreas Papassotiropoulos, Vanja Vukojevic
DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions...
September 7, 2016: Journal of Psychiatric Research
Agustín Ibáñez, Adolfo M García, Sol Esteves, Adrián Yoris, Edinson Muñoz, Lucila Reynaldo, Marcos Luis Pietto, Federico Adolfi, Facundo Manes
Multiple disorders once jointly conceived as 'nervous diseases' became segregated by the distinct institutional traditions forged in neurology and psychiatry. As a result, each field specialized in the study and treatment of a subset of such conditions. Here we propose new avenues for interdisciplinary interaction through a triangulation of both fields with social neuroscience. To this end, we review evidence from five relevant domains (facial emotion recognition, empathy, theory of mind, moral cognition, social context assessment), highlighting their common disturbances across neurological and psychiatric conditions and discussing their multiple pathophysiological mechanisms...
October 6, 2016: Social Neuroscience
S M Brooker, K T Gobeske, J Chen, C-Y Peng, J A Kessler
Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin...
October 4, 2016: Molecular Psychiatry
Gerasimos Kolaitis, Christian G Bouwkamp, Alexia Papakonstantinou, Ioanna Otheiti, Maria Belivanaki, Styliani Haritaki, Terpsihori Korpa, Zinovia Albani, Elena Terzioglou, Polyxeni Apostola, Aggeliki Skamnaki, Athena Xaidara, Konstantina Kosma, Sophia Kitsiou-Tzeli, Maria Tzetis
BACKGROUND: This is a case with multiple chromosomal aberrations which are likely etiological for the observed psychiatric phenotype consisting of attention deficit hyperactivity and conduct disorders. CASE PRESENTATION: We report on an 11 year-old boy, admitted to the pediatric hospital for behavioral difficulties and a delayed neurodevelopmental trajectory. A cytogenetic analysis and high-resolution microarray comparative genomic hybridization (CGH) analysis was performed...
2016: Child and Adolescent Psychiatry and Mental Health
Kate Wolfe, André Strydom, Deborah Morrogh, Jennifer Carter, Peter Cutajar, Mo Eyeoyibo, Angela Hassiotis, Jane McCarthy, Raja Mukherjee, Dimitrios Paschos, Nagarajan Perumal, Stephen Read, Rohit Shankar, Saif Sharif, Suchithra Thirulokachandran, Johan H Thygesen, Christine Patch, Caroline Ogilvie, Frances Flinter, Andrew McQuillin, Nick Bass
Chromosomal copy-number variations (CNVs) are a class of genetic variants highly implicated in the aetiology of neurodevelopmental disorders, including intellectual disabilities (ID), schizophrenia and autism spectrum disorders (ASD). Yet the majority of adults with idiopathic ID presenting to psychiatric services have not been tested for CNVs. We undertook genome-wide chromosomal microarray analysis (CMA) of 202 adults with idiopathic ID recruited from community and in-patient ID psychiatry services across England...
September 21, 2016: European Journal of Human Genetics: EJHG
G Pathak, M J Agostino, K Bishara, W R Capell, J L Fisher, S Hegde, B A Ibrahim, K Pilarzyk, C Sabin, T Tuczkewycz, S Wilson, M P Kelly
Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in induced pluripotent stem cell-derived hippocampal neurons originating from lithium-responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cyclic AMP and cyclic GMP. Here we determined whether decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice...
September 20, 2016: Molecular Psychiatry
J Stedehouder, S A Kushner
Schizophrenia is a debilitating psychiatric disorder characterized by positive, negative and cognitive symptoms. Despite more than a century of research, the neurobiological mechanism underlying schizophrenia remains elusive. White matter abnormalities and interneuron dysfunction are the most widely replicated cellular neuropathological alterations in patients with schizophrenia. However, a unifying model incorporating these findings has not yet been established. Here, we propose that myelination of fast-spiking parvalbumin (PV) interneurons could be an important locus of pathophysiological convergence in schizophrenia...
September 20, 2016: Molecular Psychiatry
D Leguay
This article attempts to identify and put into perspective the different approaches that could globally prevent the suffering induced by schizophrenia, from the detection of early psychosis to the impact on individual and family functioning and emotional health. Schizophrenia causes, at the community level, a number of difficult consequences and associated costs, which likely could be reduced if specific strategies, already known and documented internationally, were applied. Two areas not explored in this article: the role of medication and the issue of suicide prevention...
September 9, 2016: L'Encéphale
A Pérez-Cañamás, S Benvegnù, C B Rueda, A Rábano, J Satrústegui, M D Ledesma
Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood. Loss-of-function mutations in the acid sphingomyelinase (ASM) gene cause NPA, and result in the accumulation of sphingomyelin (SM) in lysosomes and plasma membrane of neurons. Using ASM knockout (ASMko) mice as a NPA disease model, we investigated how high SM levels contribute to neural pathology in NPA. We found high levels of oxidative stress both in neurons from these mice and a NPA patient...
September 13, 2016: Molecular Psychiatry
Golan Shahar
An integrative-psychodynamic theory of criticism in self and relationships is presented (Shahar, 2015). My theoretical starting point is the tension between Authenticity (A; our inherited potential, tantamount to Winnicott's True Self) and Self-Knowledge (SK; what we [think] we know about ourselves). Self-criticism, a formidable dimension of vulnerability to a wide array of psychopathologies, is construed as a distorted form of self-knowledge, reducing internal confusion at the expense of widening the gap between A and SK...
2016: Psychodynamic Psychiatry
A P Wingo, L M Almli, J S Stevens, T Jovanovic, T S Wingo, G Tharp, Y Li, A Lori, M Briscione, P Jin, E B Binder, B Bradley, G Gibson, K J Ressler
Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10(-8), and replicate this association in another cohort...
September 6, 2016: Molecular Psychiatry
R Zhang, M Asai, C E Mahoney, M Joachim, Y Shen, G Gunner, J A Majzoub
A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex...
September 6, 2016: Molecular Psychiatry
Luna Rodrigues Freitas-Silva, Francisco Ortega
Understanding the processes involved in the development of mental disorders has proven challenging ever since psychiatry was founded as a field. Neuroscience has provided new expectations that an explanation will be found for the development of mental disorders based on biological functioning alone. However, such a goal has not been that easy to achieve, and new hypotheses have begun to appear in neuroscience research. In this article we identify epigenetics, neurodevelopment, and plasticity as the principal avenues for a new understanding of the biology of mental phenomena...
2016: Cadernos de Saúde Pública
Eve S Fields, Raymond A Lorenz, Joel G Winner
This report describes two cases in which pharmacogenomic testing was utilized to guide medication selection for difficult to treat patients. The first patient is a 29-year old male with bipolar disorder who had severe akathisia due to his long acting injectable antipsychotic. The second patient is a 59-year old female with major depressive disorder who was not responding to her medication. In both cases, a proprietary combinatorial pharmacogenomic test was used to inform medication changes and improve patient outcomes...
2016: Pharmacogenomics and Personalized Medicine
A Caccamo, E Ferreira, C Branca, S Oddo
The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β (Aβ) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD...
August 30, 2016: Molecular Psychiatry
Brenda Finucane, Scott M Myers
PURPOSE OF REVIEW: Psychiatry is steadily moving toward a new conceptualization of brain disorders that blurs long-held diagnostic distinctions among neurodevelopmental and psychiatric conditions, including autism. Genomic discoveries are driving these changing perceptions, yet there has so far been minimal impact on traditional genetic counseling practices that continue to view autism through the lens of a dichotomous, all-or-none risk model. RECENT FINDINGS: High rates of comorbidity exist across autism spectrum disorder, schizophrenia, intellectual disability, and other brain-based disorders...
2016: Current Genetic Medicine Reports
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