The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies

Genetic-neuroimaging paradigms could provide insights regarding the pathophysiology of bipolar disorder (BD). Nevertheless, findings have been inconsistent across studies. A systematic review of gene-imaging studies involving individuals with BD was conducted across electronic major databases from inception until January 9th, 2017. Forty-four studies met eligibility criteria (N=2122 BD participants). Twenty-six gene variants were investigated across candidate gene studies and 4 studies used a genome-wide association approach. Replicated evidence (i.e. in >2 studies) suggests that individuals with BD carrying the BDNF Val66Met risk allele could have reduced hippocampal volumes compared to non-carriers. This review underscores the potential of gene-neuroimaging paradigms to provide mechanistic insights for BD. However, this systematic review found a single replicated finding. Suggestions to improve the reproducibility of this emerging field are provided, including the adoption of a trans-diagnostic approac

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation

© The Author(s), 2022. Published by Cambridge University Press. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.Background: Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. Methods: A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, 'at risk mental state' or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. Results: We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). Conclusions: Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.VT was supported by a Fundação para a Ciência e Tecnologia (FCT) PhD fellowship (PD/BD/114460/2016) and hired on the FCT DSAIPA/DS/0065/2018 grant. DP was supported, during this work, by the European Commission Seventh Framework Programme Marie Curie Career Integration Grant FP7-PEOPLE-2013-CIG-631952, the 2016 Bial Foundation Psychophysiology Grant – Ref. 292/16, and the FCT IF/00787/2014, LISBOA-01-0145-FEDER-030907, DSAIPA/DS/0065/2018 and UIDB/00645/2020 grants, and the Instituto de Medicina Molecular (iMM) Lisboa Director's Fund Breakthrough Idea Grant 2016.info:eu-repo/semantics/publishedVersio

Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk

AbstractEvidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders

The Role of Astrocytes in the Pathophysiology of Schizophrenia.

A glutamate hypothesis of schizophrenia emerged based on pharmacological evidence that N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), can induce symptoms similar to those seen in schizophrenia. Subsequently, abnormal expression of various neuronal molecules associated with the glutamate synapse has been reported in schizophrenia. Astrocytes, a prominent glial cell in the brain, play a significant role in maintaining the structure and integrity of neural tissue and in facilitating excitatory neurotransmission, therefore, any breakdown in the structure or function of astrocytes could disrupt neuronal signaling and disturb brain function. I studied structural and functional molecules in astrocytes to determine 1) whether astrocytes are themselves globally compromised in schizophrenia, and 2) whether abnormal expression of glutamatergic molecules in astrocytes could be a contributing factor to brain dysfunction in this illness. I examined the expression of molecular markers of astrocytes as a measure of the integrity of these cells in schizophrenia. S100B, a calcium binding protein previously shown to be increased in the plasma and CSF of patients with schizophrenia, was not altered. I found that the intermediate-filament glial fibrillary acidic protein (GFAP), a component of the astrocyte cytoskeleton, was significantly altered in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in schizophrenia. I also measured the expression of two astrocytic enzymes involved in glutamate function: glutamine synthetase, involved in recycling synaptic glutamate, and serine racemase, which synthesizes the NMDA receptor co-agonist D-serine. Glutamine synthetase was significantly decreased in the superior temporal gyrus and ACC, and protein expression of serine racemase was increased in the hippocampus in schizophrenia. This was the first study to demonstrate altered expression of glutamine synthetase in these brain regions, and the first report of serine racemase expression abnormalities in schizophrenia. These findings suggest that astrocytes contribute to the pathophysiology of schizophrenia and that astrocytic molecules involved in cytoskeletal integrity and glutamatergic function are compromised in this illness. Schizophrenia is a complex illness that requires a reappraisal of the existing neuronal model to include an astrocytic hypothesis of dysfunction, which could lead to a better understanding of schizophrenia, and provide novel treatment strategies in this illness.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/55679/2/asteffek_1.pd

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS

Early Identification and Intervention of Schizophrenia: Insight From Hypotheses of Glutamate Dysfunction and Oxidative Stress

Schizophrenia is a severe mental disorder which leads to functional deterioration. Early detection and intervention are vital for better prognosis. However, the diagnosis of schizophrenia still depends on clinical observation to date. Without reliable biomarkers, schizophrenia is difficult to detect in its early phase. Further, there is no approved medication for prodromal schizophrenia because current antipsychotics fail to show satisfactory efficacy and safety. Therefore, to develop an effective early diagnostic and therapeutic approach for schizophrenia, especially in its prodromal phase, is crucial. Glutamate signaling dysfunction and dysregulation of oxidative stress have been considered to play important roles in schizophrenic prodrome. The N-methyl-D-aspartate receptor (NMDAR) is one of three types of ionotropic glutamate receptors. In this article, we reviewed literature regarding NMDAR hypofunction, oxidative stress, and the linkage between both in prodromal schizophrenia. The efficacy of NMDAR enhancers such as D-amino acid oxidase inhibitor was addressed. Finally, we highlighted potential biomarkers related to NMDAR and oxidative stress regulation, and therefore suggested the strategies of early detection and intervention of prodromal schizophrenia. Future larger-scale studies combining biomarkers and novel drug development for early psychosis are warranted

Dopamine neurotoxicity, oxidative stress and schizophrenia : in vitro and in vivo studies of peroxisomal reactions to increased dopamine

Signs of neurodegeneration are commonly found in schizophrenic patients, albeit still unclear, why they occur and whether they are a cause or rather an effect of schizophrenia. Although there are numerous studies supporting either theory, the working hypothesis of this thesis is that an overactivity of mesolimbic dopaminergic pathways leads to dopamine neurotoxicity in terms of an increased production of reactive oxygen species (ROS), in time leading to oxidative stress and thereby to so-called atypical neurodegeneration. This in turn negatively influences i.a. frontal glutamate neurotransmission, thereby linking the proposed schizophrenia-models of hyperdopaminergia and hypoglutamatergia. A key player in the body’s antioxidant capacity is the peroxisome. This cell organelle is involved in both enzymatic (e.g. through the H2O2-degrading enzyme catalase) as well as non-enzymatic antioxidant metabolism. Its role in schizophrenia has, however, only been poorly examined, even though peroxisomes additionally are the only known source to-date of major enzymes for the degradation of cofactors of NMDA-receptors (including NMDA itself). Changes in peroxisomal metabolism and abundance therefore influence both the brain’s capacity to degrade ROS as well as the functionality of its NMDA receptors and vice versa. This thesis therefore examines the reactions of peroxisomes to increased dopamine. Since peroxisomes are involved in a number of other metabolic functions apart from antioxidant defense, their enzyme content is highly heterogeneous. Catalase and ABCD3 are generally used as markers for peroxisomes. Their abundance is, however, highly dependent on metabolic demands and therefore varies extremely between as well as within different organs, tissues and cells. Especially in the brain, both catalase and ABCD3 are barely detectable, thereby leading to a marked underestimation of true peroxisomal abundance and distribution. In the first part of this thesis it was therefore attempted to establish a new peroxisomal marker, peroxin 14 (Pex14p), which is part of a docking complex on the peroxisomal membrane relevant for import of all matrix proteins and therefore independent of individual peroxisomal metabolism. Using various morphological methods in a large variety of organs, tissues and cell types from a number of different species it could be shown that Pex14p is indeed present in the membrane of every healthy peroxisome and is expressed in similarly high levels in tissue sections and cell cultures of different organs and species. As Pex14p is also highly suited as a peroxisomal marker in all neuronal tissue, post mortem brain sections of schizophrenic patients and controls were analyzed regarding the abundance and distribution of peroxisomes as well as catalase. The results were, however, inconclusive, wherefore the reactions of peroxisomes to increased dopamine were analyzed under more controllable conditions within the second part of this thesis. The effects of dopamine in vitro were examined using primary murine neuronal and astrocyte cell cultures and the in vivo-effects in a pharmacological mouse model (through subchronic systemic administration of the selective, non-competitive NMDAR-antagonist MK-801). Analyses of gene expression patterns from the brains of the animals show i.a. an activation of antioxidant pathways in MK-801-treated animals compared to vehicle-treated controls as well as an increase in mRNA copies of enzymes involved in NMDAR-cofactor degradation. Morphological experiments show that dopamine changes peroxisomal reactions and neuronal morphology specifically and only in intact neuron-astrocyte interactions, mimicking the atypical neurodegeneration found in schizophrenic patients. Additionally, increased levels of selected antioxidant enzymes were found to be increased in the brains of MK-801-treated animals. It can therefore be concluded that dopamine does indeed lead to increased ROS production in the brain, which is, however, initially still countered by an increase in antioxidant defense mechanisms. This strengthens the initial hypothesis that oxidative stress (i.e. the state of disequilibrium between ROS production and antioxidant defense) is an effect rather than a cause of schizophrenia. Finally, the dopamine-related increase in the expression of genes encoding for enzymes degrading NMDAR-cofactors, thereby leading to a decrease of NMDAR-mediated neurotransmission, shows that hyperdopaminergia and hypoglutamatergia in schizophrenia are not separate entities, but rather influence, uphold and even exacerbate each other. This led to the proposition of a new integrative model of the etiopathogenesis of schizophrenia, linking both hyperdopaminergia and hypoglutamatergia together.Bezüglich der bei Schizophrenen gefundenen Neurodegeneration ist die Frage nach Ursache und Wirkung unklar. Viele Befunde erlauben jedoch die Hypothese, dass, aufgrund einer Überaktivität des mesolimbischen Dopaminsystems, innerhalb und außerhalb der Neurone eine neurotoxische Wirkung des Dopamins und seiner Metaboliten im Sinne der Produktion reaktiver Sauerstoffspezies (ROS) auftritt. Neben den Mitochondrien und dem Zytoplasma spielt das Peroxisom eine wesentliche Rolle in der enzymatischen (z.B. durch Katalase) und nicht-enzymatischen antioxidativen Abwehr. Die Konzentration des klassischen peroxisomalen Markerenzyms Katalase ist jedoch in Neuronen ausgesprochen niedrig, weshalb im ersten Schritt der Arbeit ein neues Markerprotein für Peroxisomen (Peroxin 14, Pex14p) an einer Vielzahl verschiedener Gewebe und Zellen mittels Proteinlabelingmethoden für Elektronen-, Licht- und Fluoreszenzmiskroskopie etabliert wurde. Über diese neue Methode war es nun möglich, Peroxisomen auch im Nervengewebe unabhängig ihres Katalasegehaltes zu untersuchen. Wir haben daher die Anzahl an Peroxisomen und Katalase an postmortem Hippokampusschnitten von Schizophrenen und Kontrollen verglichen. Aufgrund methodologischer Einschränkungen waren die Befunde jedoch uneindeutig. Im nächsten Schritt wurden Mischkulturen muriner Neurone und Astrozyten mit unterschiedlichen Dopaminkonzentrationen inkubiert, wonach sich eine Erhöhung der Katalasemenge vor allem in Astrozyten, begleitet von einer Umverteilung der Peroxisomen aus den Dendriten in die Somata ohne signifikante Zelltoderhöhung zeigte. Wir wiederholten diese Experimente daher mit reinen Astrozytenkulturen und fanden selbst bei Erhöhung der Dopaminkonzentration und Inkubationsdauer keine Unterschiede zu Vehikel-behandelten Kulturen. Dies spricht für die antitoxische Wirkung der Astrozyten und die Spezifität der Reaktionen aus den ersten Zellkulturen für intakte neuroastrozytäre Verbände. In darauf aufbauenden Tierversuchen untersuchten wir die Erhöhung des mesolimbischen Dopamins in männlichen Wildtypmäusen durch Gabe des NMDAR-Antagonisten MK-801. Im Anschluss an Behandlungsdauern von 1h-72h wurden die Gehirne entnommen und für morphologische Analysen oder Extraktion der RNAs für Expressionsanalysen verwandt. Unsere Befunde stärken die Annahme, dass Dopamin neurodegenerative Veränderungen hervorruft und diese erst im späteren Krankheitsverlauf auftreten und daher vermutlich nicht an der Äthiopathogenese der Schizophrenie beteiligt, sondern eher als Folgeerscheinung der Dopamin-Neurotoxizität anzusehen sind