Biology subjects

Vernon, A. C.

Publications and source records attributed to Vernon, A. C..

21 records · Page 2Linked to original sources

bioRxiv2019

Region-specific and dose-specific effects of chronic haloperidol exposure on Ro15-4513 GABA-A receptor binding sites in the rat brain

Post-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) subunits, including 5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABAAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a 1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.

neuroscience↗

bioRxiv2018

Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic 5-nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.

neuroscience↗

bioRxiv2018

Maternal immune activation specifically increases diagonal domain volume in the rat brain during early postnatal development

Maternal immune activation (MIA) is consistently associated with elevated risk for multiple psychiatric and neurological disorders in the affected offspring. Converging lines of evidence from humans and animal models suggest a link between MIA and early entry into an atypical neurodevelopmental trajectory characterised by time- and sex-dependent abnormalities in brain structure and function. However to date, no such studies have investigated the brain-wide impact of MIA in the early post-weaning period, a critical and dynamic window of brain development. To address this, we acquired high-resolution ex vivo structural and diffusion tensor imaging (DTI) images from Wistar rat brains on postnatal day (PD) 21 following exposure to the viral mimetic poly (I:C) or sterile saline on gestational day (GD) 15 using a recently validated protocol. Using a combination of atlas-based segmentation and tensor based morphometry analysis we observed that MIA resulted in a significant increase in the relative volume of the diagonal domain (FDR q<0.1). Additional trend-level volume increases (p<0.05 uncorrected) were also found for the olfactory structures and preoptic area. Although not significant after FDR correction, we found trend-level evidence (p<0.05 uncorrected) for MIA x sex interactions in the volume of the diagonal domain, nucleus accumbens, pineal gland and anterior commissure. In contrast to volume, we found no evidence for microstructural alterations in our DTI dataset at PD21. These data provide new insights into the specific effects of MIA early in development, highlighting in particular, the diagonal domain as a target for future studies.

neuroscience↗