A systematic review of the effect of genes mediating neurodevelopment and neurotransmission on brain morphology: Focus on schizophrenia

John, John P.; Thirunavukkarasu, Priyadarshini; Halahalli, Harsha N.; Purushottam, Meera; Jain, Sanjeev

doi:10.1016/j.npbr.2014.11.003

Cited by 3 publications

(3 citation statements)

References 287 publications

(261 reference statements)

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“…For example, schizophrenia-associated mutations in reelin (RELN) and disrupted in schizophrenia1 (DISC1) can cause defects in neuronal migration ( Kamiya et al, 2005 ), dendritic organization, and remodeling of synapses ( Arnold, 1999 ). In addition, protocadherin 12 (PCDH12) linked to schizophrenia ( Gregorio et al, 2009 ) has been implicated in neuronal differentiation and synaptogenesis ( John et al, 2015 ). In line with these findings, another report has suggested the possibility of neuropsychiatric diseases associated with genetic perturbations in the cell adhesion molecule (CAM) pathway, including NRXN1, CNTNAP, and CASK ( Redies et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions

Park¹,

Park²,

Lee³

2017

Molecules and Cells

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Proper synaptic function in neural circuits requires precise pairings between correct pre- and post-synaptic partners. Errors in this process may underlie development of neuropsychiatric disorders, such as autism spectrum disorder (ASD). Development of ASD can be influenced by genetic factors, including copy number variations (CNVs). In this study, we focused on a CNV occurring at the 16p11.2 locus in the human genome and investigated potential defects in synaptic connectivity caused by reduced activities of genes located in this region at Drosophila larval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation of rolled, a Drosophila homolog of human mitogen-activated protein kinase 3 (MAPK3) at the 16p11.2 locus, caused ectopic innervation of axonal branches and their abnormal defasciculation. The specificity of these phenotypes was confirmed by expression of wild-type rolled in the mutant background. Albeit to a lesser extent, we also observed ectopic innervation patterns in mutants defective in Cdk2, Gαq, and Gp93, all of which were expected to interact with Rolled MAPK3. A further genetic analysis in double heterozygous combinations revealed a synergistic interaction between rolled and Gp93. In addition, results from RT-qPCR analyses indicated consistently reduced rolled mRNA levels in Cdk2, Gαq, and Gp93 mutants. Taken together, these data suggest a central role of MAPK3 in regulating the precise targeting of presynaptic axons to proper postsynaptic targets, a critical step that may be altered significantly in ASD.

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Section: Introductionmentioning

confidence: 99%

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions

Park¹,

Park²,

Lee³

2017

Molecules and Cells

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“…Therefore, the results of the present study indicate that the relationship between brain volumetric alterations and the schizophrenia phenotype cannot be conceptualized using a simplistic (cause-effect) framework. On the contrary, in silico models that simulate gene-gene (epistatic) and gene-environment (epigenetic) interactions affecting brain morphology might provide us with a more comprehensive understanding regarding complexities underlying the brain morphometric alterations associated with schizophrenia [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

A systematic examination of brain volumetric abnormalities in recent-onset schizophrenia using voxel-based, surface-based and region-of-interest-based morphometric analyses

John

Lukose

Bagepally

et al. 2015

J Negat Results BioMed

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BackgroundBrain morphometric abnormalities in schizophrenia have been extensively reported in the literature. Whole-brain volumetric reductions are almost universally reported by most studies irrespective of the characteristics of the samples studied (e.g., chronic/recent-onset; medicated/neuroleptic-naïve etc.). However, the same cannot be said of the reported regional morphometric abnormalities in schizophrenia. While certain regional morphometric abnormalities are more frequently reported than others, there are no such abnormalities that are universally reported across studies. Variability of socio-demographic and clinical characteristics across study samples as well as technical and methodological issues related to acquisition and analyses of brain structural images may contribute to inconsistency of brain morphometric findings in schizophrenia. The objective of the present study therefore was to systematically examine brain morphometry in patients with recent-onset schizophrenia to find out if there are significant whole-brain or regional volumetric differences detectable at the appropriate significance threshold, after attempting to control for various confounding factors that could impact brain volumes.MethodsStructural magnetic resonance images of 90 subjects (schizophrenia = 45; healthy subjects = 45) were acquired using a 3 Tesla magnet. Morphometric analyses were carried out following standard analyses pipelines of three most commonly used strategies, viz., whole-brain voxel-based morphometry, whole-brain surface-based morphometry, and between-group comparisons of regional volumes generated by automated segmentation and parcellation.ResultsIn our sample of patients having recent-onset schizophrenia with limited neuroleptic exposure, there were no significant whole brain or regional brain morphometric abnormalities noted at the appropriate statistical significance thresholds with or without including age, gender and intracranial volume or total brain volume in the statistical analyses.ConclusionsIn the background of the conflicting findings in the literature, our findings indicate that brain morphometric abnormalities may not be directly related to the schizophrenia phenotype. Analysis of the reasons for the inconsistent results across studies as well as consideration of alternate sources of variability of brain morphology in schizophrenia such as epistatic and epigenetic mechanisms could perhaps advance our understanding of structural brain alterations in schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12952-015-0030-z) contains supplementary material, which is available to authorized users.

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“…The ontology of mental health problems is an area of long-standing debate. This has been fuelled by strong claims of a genetic basis to mental health problems, particularly in relation to the more serious difficulties such as schizophrenia and psychosis (John, Thirunavukkarasu, Halahalli, Purushottam, & Jain, 2015). The result of this biological framework has influenced practice at a service level, with medication the primary treatment offered to this client group.…”

Section: Introductionmentioning

confidence: 99%

Mental health clinicians’ beliefs about the causes of psychosis: Differences between professions and relationship to treatment preferences

Carter

Read

Pyle

et al. 2017

Int J Soc Psychiatry

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Clients were twice as likely to be offered medication compared to CBT. Clinicians held a multifactorial model of aetiology, but were more likely to endorse psychosocial causes than biological factors. Clinicians with psychosocial beliefs were more likely to rate CBT as effective, whereas those with biological models were more likely to endorse the helpfulness of medication. Clinicians adopt a multi-causal approach when conceptualising the aetiology of psychosis and these beliefs were related to opinions about the helpfulness of treatment. Beliefs about the aetiology of their client's experiences could blind clinicians to the benefits of offering different approaches.

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A systematic review of the effect of genes mediating neurodevelopment and neurotransmission on brain morphology: Focus on schizophrenia

Cited by 3 publications

References 287 publications

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions

MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions

A systematic examination of brain volumetric abnormalities in recent-onset schizophrenia using voxel-based, surface-based and region-of-interest-based morphometric analyses

Mental health clinicians’ beliefs about the causes of psychosis: Differences between professions and relationship to treatment preferences

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