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Common polymorphisms in dopamine related genes combine to produce a “schizophrenia-like” prefrontal hypoactivity

Common polymorphisms in dopamine related genes combine to produce a “schizophrenia-like” prefrontal hypoactivity

Forty-three healthy adults and 27 people with schizophrenia received an fMRI scan while completing an emotional response inhibition test. Blood samples were collected and DNA was genotyped using Taqman SNP assays. The number of “risk” alleles was tallied in each participant to generate an oligogenic score which was used as a predictor of brain activation. We also tested whether task related brain activity was related to antipsychotic dosage in schizophrenia.

People with schizophrenia showed a significantly reduced activity during inhibition of responses to negative words in left insula, left BA 10, right BA 10, right anterior cingulate, and right BA 9 compared to healthy adults. We detected a significant linear association between increasing prefrontal dopamine risk allele load and reduced activation in the left insula, bilateral BA10, and right BA9 in healthy adults and no such relationship in schizophrenia. We observed a negative association between daily chlorpromazine equivalent dose and dorsolateral prefrontal activation in schizophrenia.

These results provide the first evidence that genetic variation controlling DRD2 receptor characteristics and synaptic dopaminergic availability combine to shape prefrontal cortex neural responses during cognitive-affective challenges. Thus, dopaminergic genes can additively combine in healthy people to produce the hypofrontality endophenotype characteristic of schizophrenia. Antipsychotics could be an overriding environmental factor obscuring dopaminergic genetic effects in schizophrenia.

Conference: MAPrc
Areas of Interest / Categories: MAPrc 2015

MAPrc 2015

Maternal immune activation impacts on the kynurenine pathway in preadolescent offspring: Preventive effects of anti-inflammatory treatment.

Kynurenic acid (KYNA), a glia-derived metabolite of the kynurenine pathway (KP) of tryptophan degradation, is an antagonist at glutamate NMDA and a7 nicotinic acetylcholine receptors. Abnormalities in the KP have been described in patients with schizophrenia. Cyclo-oxygenese-2 (COX-2) inhibitors show considerable promise in treating early (but not late) stage schizophrenia and preclinical studies suggest that COX-2 inhibitors decrease KYNA in the brain.

The Epidermal Growth Factor system in schizophrenia and its relation to treatment resistance

Up to 45% of patients with schizophrenia are treatment resistant to conventional drugs leaving clozapine as the only effective option. Its severe side-effects however limit it to a late stage option and the development of a biomarker to predict treatment response would be of high clinical utility. Our previous data demonstrate clozapine augments epidermal growth factor receptor (EGFR) signalling and hence we examined if EGF levels may be altered in treatment resistant schizophrenia (TRS) and are influenced by clozapine treatment. To determine if EGF levels are influenced by clozapine in TRS and can serve as a biomarker for clozapine response. Serum EGF levels were measured by ELISA in patients with TRS at baseline, 2, 6 and 26 weeks of clozapine treatment and in age and sexed matched healthy controls. Positive and Negative Syndrome Scale (PANSS) and CGI data were collected at baseline, 6 and 26 weeks.

Altered cell migration in patient-derived stem cell model of schizophrenia.

Evidence from genetic association studies implicate genes involved in neural migration associated with schizophrenia risk. Neural stem/progenitor cell cultures (neurosphere-derived cells) from olfactory mucosa of schizophrenia patients have significantly dysregulated expression of genes in focal adhesion kinase signalling, a key pathway regulating cell adhesion and migration. The aim of this study was to investigate whether olfactory neurosphere-derived cells from schizophrenia patients have altered cell adhesion, cell motility, and focal adhesion dynamics. Olfactory neurosphere-derived cells from nine male schizophrenia patients and nine male healthy control subjects were used. Cells were assayed for cell adhesion and cell motility and analysed for integrins and focal adhesion kinase proteins. Focal adhesions were counted and measured in fixed cells and time-lapse imaging was used to assess cell motility and focal adhesion dynamics.

Interaction of maternal immune activation and adolescent cannabinoid exposure enhances changes in miRNA expression in the adult entorhinal cortex.

Post-mortem analyses of cortical brain tissue in schizophrenia have been shown to display epigenetic changes that reflect early life experience. These affect the regulation of gene expression at the level of transcription, through changes in chromatin structure; and post-transcriptionally through non-coding RNAs, such as microRNA (miRNA). The aim of the current study was to investigate the role of miRNA in the brains’ response to maternal immune activation and adolescent cannabis exposure, alone and in combination, as both have been identified as environmental risk factors for schizophrenia.

Can Neuropsychological Profile (RBANS) Predict Co-Morbid Traumatic Brain Injury and Psychosis?

NOTE: Only available in Mp3 audio file. Traumatic insanity has been acknowledged since Meyer (1904), however, Psychosis Following Traumatic Brain Injury (PFTBI) has received modest empirical investigation, and is subsequently poorly understood, identified, and treated. Systematic and standardised neuropsychological research of PFTBI has not been reported, with work relying on retrospective chart reviews, case studies, and loosely defined self-reported Traumatic Brain Injury (TBI).