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.
Pregnant Wistar rats received an intravenous injection of polyriboinosinic-polyribocytidilic acid (poly I:C) or vehicle on embryonic day 15. Beginning post-natal day (PND) 35, male offspring were treated daily with the synthetic cannabinoid HU210, or vehicle, for 14 days and euthanized on PND 55. Whole genome miRNA microarrays were performed on the left and right entorhinal cortex as this region has been shown to display altered volumes and other anatomical abnormalities in schizophrenia. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited significant differences in miRNA expression, compared to either treatment alone, where only a small effect was observed for each treatment with respect to untreated controls.
This effect was dominated by a large subgroup of miRNA differentially transcribed from a single imprinted locus on chromosome 6q32. In humans, the syntenic locus (14q32) encodes a large proportion of miRNAs found to be differentially expressed in white blood cells from patients with schizophrenia. These miRNA are predicted to target genes highly enriched in pathways repeatedly implicated in the pathophysiology of schizophrenia including Wnt, ErbB and MAP kinase signalling. These results suggest the interaction of both early and late environmental insults, can enhance changes in miRNA expression in the EC, with possible implications for schizophrenia in adulthood.
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.
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.
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.
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).
The dopamine system plays a crucial role in mediating cognitive and affective processes. Aberrant dopamine neurotransmission is also thought to underlie the symptoms of schizophrenia. Dopamine-dependent prefrontal response relies on the regulation of both dopamine availability and the relative balance of D1/D2 receptor mediated action. This study aimed to determine the extent to which the catechol-O-methyltransferase (COMT) val108/158met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) polymorphisms combine additively to determine prefrontal brain activity during cognitive-affective processing in healthy people and in schizophrenia.