SNAP-25a/b Isoform Levels in Human Brain Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex
We examined the SNAP-25 isoform mRNA and protein levels in postmortem cortex Brodmann's area 9 (BA9) and BA24 (n = 29). Subjects were divided by psychiatric diagnosis, clinical variables including mood state in the last week of life and lifetime impulsiveness. We found affected subjects with a diagnosis of alcohol use disorder (AUD) had a lower level of SNAP-25b BA24 protein compared to those without AUD. Hispanic subjects had lower levels of SNAP-25a, b and BA9 mRNA than Anglo-American subjects. Subjects who smoked had a total pan (total) SNAP-25 BA9/BA24 ratio. Subjects in the group with a low level of anxious-psychotic ...
Source: Molecular Neuropsychiatry - November 30, 2015 Category: Neuroscience Source Type: research
Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia
Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some S...
Source: Molecular Neuropsychiatry - October 28, 2015 Category: Neuroscience Source Type: research
Neural Correlates of Schizophrenia Negative Symptoms: Distinct Subtypes Impact Dissociable Brain Circuits
Conclusions: Individual symptoms were related to different patterns of functional activation during the oddball task, suggesting that individual symptoms might arise from distinct neural mechanisms. This work has potential to inform interventions that target these symptom-related neural disruptions.Mol Neuropsychiatry 2015;1:191-200 (Source: Molecular Neuropsychiatry)
Source: Molecular Neuropsychiatry - October 16, 2015 Category: Neuroscience Source Type: research
Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness
In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.Mol Neuropsychiat...
Source: Molecular Neuropsychiatry - October 6, 2015 Category: Neuroscience Source Type: research
Association Study of Genotype by Depressive Response during Acute Tryptophan Depletion in Subjects Recovered from Major Depression
Conclusions: ATD may help identifying the biological subtypes of MDD. These data are consistent with imaging reports implicating 5-HT2A receptor function in ATD phenotypes.Mol Neuropsychiatry 2015;1:165-174 (Source: Molecular Neuropsychiatry)
Source: Molecular Neuropsychiatry - September 24, 2015 Category: Neuroscience Source Type: research
Tourette Syndrome: Bridging the Gap between Genetics and Biology
Tourette syndrome is a childhood neuropsychiatric disorder, which presents with disruptive motor and vocal tics. The disease also has a high comorbidity with obsessive-compulsive disorder and attention deficit hyperactivity disorder, which may further increase the distress experienced by patients. Current treatments act with varying efficacies in alleviating symptoms, as the underlying biology of the disease is not fully understood to provide precise therapeutic targets. Moreover, the genetic complexity of the disorder presents a substantial challenge to the identification of genetic alterations that contribute to the Tour...
Source: Molecular Neuropsychiatry - September 5, 2015 Category: Neuroscience Source Type: research
Clinical Utility of Combinatorial Pharmacogenomics-Guided Antidepressant Therapy: Evidence from Three Clinical Studies
DNA of 258 patients with treatment-resistant depression was collected in three 8-10 week, two-arm, prospective clinical trials. Forty-four allelic variations were measured in genes for the cytochrome P450 (CYP) enzymes CYP2D6, CYPC19, and CYP1A2, the serotonin transporter (SLC6A4), and the 5-HT2A receptor (HTR2A). The combinatorial pharmacogenomic (CPGx™) GeneSight test results were provided to clinicians to support medication changes from baseline (guided arm), or they were provided at the end of each study to clinicians of unguided patients who were treated as usual (TAU). TAU subjects who at baseline were prescribed m...
Source: Molecular Neuropsychiatry - July 30, 2015 Category: Neuroscience Source Type: research
Characterization of a Novel Mutation in SLC1A1 Associated with Schizophrenia
We have recently described a hemi-deletion on chromosome 9p24.2 at the SLC1A1 gene locus and its co-segregation with schizophrenia in an extended Palauan pedigree. This finding represents a point of convergence for several pathophysiological models of schizophrenia. The present report sought to characterize the biological consequences of this hemi-deletion. Dual luciferase assays demonstrated that the partially deleted allele (lacking exon 1 and the native promoter) can drive expression of a 5′-truncated SLC1A1 using sequence upstream of exon 2 as a surrogate promoter. However, confocal microscopy and electrophysiologica...
Source: Molecular Neuropsychiatry - July 7, 2015 Category: Neuroscience Source Type: research
Genetic and Morphological Features of Human iPSC-Derived Neurons with Chromosome 15q11.2 (BP1-BP2) Deletions
Conclusions: The 15q11.2 (BP1-BP2) deletion is associated with a reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated with altered iPSC-neuron dendritic morphology.Mol Neuropsychiatry 2015;1:116-123 (Source: Molecular Neuropsychiatry)
Source: Molecular Neuropsychiatry - June 24, 2015 Category: Neuroscience Source Type: research
Polymorphism within a Neuronal Activity-Dependent Enhancer of NgR1 Is Associated with Corpus Callosum Morphology in Humans
The human Nogo-66 receptor 1 (NgR1) gene, also termed Nogo receptor 1 or reticulon 4 receptor (RTN4R) and located within 22q11.2, inhibits axonal growth and synaptic plasticity. Patients with the 22q11.2 deletion syndrome show multiple changes in brain morphology, with corpus callosum (CC) abnormalities being among the most prominent and frequently reported. Thus, we hypothesized that, in humans, NgR1 may be involved in CC formation. We focused on rs701428, a single nucleotide polymorphism of NgR1, which is associated with schizophrenia. We investigated the effects of the rs701428 genotype on CC structure in 50 healthy par...
Source: Molecular Neuropsychiatry - June 24, 2015 Category: Neuroscience Source Type: research
Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex
Recent progress in psychiatric research has accumulated many mouse models relevant to developmental neuropsychiatric disorders using numerous genetic and environmental manipulations. Since the prefrontal cortex (PFC) is essential for cognitive functions whose impairments are central symptoms associated with the disorders in humans, it has become crucial to clarify altered developmental processes of PFC circuits in these mice. To that end, we aimed to understand a sequence of molecular events during normal mouse PFC development. Expression profiles for representative genes covering diverse biological processes showed that w...
Source: Molecular Neuropsychiatry - June 9, 2015 Category: Neuroscience Source Type: research
Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates
The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the pathophysiology and treatment of schizophrenia. Genome-wide changes in prefrontal cortex gene expression revealed alterations of 146 transcripts in the PCP treatment group compared to vehicle controls. Dysregulated genes were enriched in identified classes implicated in neurological and genetic dis...
Source: Molecular Neuropsychiatry - June 5, 2015 Category: Neuroscience Source Type: research
Mood Stabilizers and the Influence on Global Leukocyte DNA Methylation in Bipolar Disorder
Little is known about the relationship between treatments for bipolar disorder (BD), their therapeutic responses and the DNA methylation status. We investigated whether global DNA methylation levels differ between healthy controls and bipolar patients under different treatments. Global DNA methylation was measured in leukocyte DNA from bipolar patients under lithium monotherapy (n = 29) or combination therapy (n = 32) and from healthy controls (n = 26). Lithium response was assessed using the Alda scale. Lithium in monotherapy was associated with hypomethylation (F = 4.63, p = 0.036). Lithium + valproate showed a hypermeth...
Source: Molecular Neuropsychiatry - June 3, 2015 Category: Neuroscience Source Type: research
What Have Mass Spectrometry-Based Proteomics and Metabolomics (Not) Taught Us about Psychiatric Disorders?
Understanding the molecular causes and finding appropriate therapies for psychiatric disorders are challenging tasks for research; -omics technologies are used to elucidate the molecular mechanisms underlying brain dysfunction in a hypothesis-free manner. In this review, we will focus on mass spectrometry-based proteomics and metabolomics and address how these approaches have contributed to our understanding of psychiatric disorders. Specifically, we will discuss what we have learned from mass spectrometry-based proteomics and metabolomics studies in rodent models and human cohorts, outline current limitations and discuss ...
Source: Molecular Neuropsychiatry - May 11, 2015 Category: Neuroscience Source Type: research
NextGen Brain Microdialysis: Applying Modern Metabolomics Technology to the Analysis of Extracellular Fluid in the Central Nervous System
Microdialysis is a powerful method for in vivo neurochemical analyses. It allows fluid sampling in a dynamic manner in specific brain regions over an extended period of time. A particular focus has been the neurochemical analysis of extracellular fluids to explore central nervous system functions. Brain microdialysis recovers neurotransmitters, low-molecular-weight neuromodulators and neuropeptides of special interest when studying behavior and drug effects. Other small molecules, such as central metabolites, are typically not assessed despite their potential to yield important information related to brain metabolism and a...
Source: Molecular Neuropsychiatry - April 29, 2015 Category: Neuroscience Source Type: research
