Biology subjects

Modinos, G.

Publications and source records attributed to Modinos, G..

6 recordsLinked to original sources

bioRxiv2024

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain function that are associated with schizophrenia spectrum disorders (SSD) are already present in young adults at clinical high-risk for psychosis (CHR-P), yet the cellular and molecular determinants of these alterations are not well understood. Here, combining regional cerebral blood flow (rCBF) data with existing transcriptomic and neurotransmitter data, we show that cell-types involved in stress response and inflammation, as well as the dopamine, acetylcholine, GABAA and NMDA receptor systems, align as shared and distinct cellular and neurochemical signatures of rCBF phenotypes in people with SSD and those at CHR-P. Decoding the biological pathways involved in neuroimaging-based psychosis phenotypes may provide a basis for the development of novel interventions.

neuroscience↗

bioRxiv2022

Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

Converging lines of evidence suggest that dysfunction of cortical parvalbumin-expressing (PV+) GABAergic interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and levels of glutamatergic metabolites, and decreases in binding of GABAA 5 receptors and the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between PV+ interneuron dysfunction and these neuroimaging readouts have yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal PV+ interneurons leads to several synaptic, behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this PV+ interneuron disruption affects the hippocampal in vivo neuroimaging readouts in the Erbb4 model. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n=12) and their wild-type littermates (Erbb4F/F, n=12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated CBF and glutamine levels, as well as decreased SV2A density compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical PV+ interneurons in mice recapitulate some of the key neuroimaging findings in psychosis patients, and link PV+ interneuron deficits to non-invasive, translational measures of brain function and neurochemistry that can be used across species.

neuroscience↗

bioRxiv2022

Molecular and connectomic vulnerability shape cross-disorder cortical abnormalities

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21 000 patients and N = 26 000 controls, collected using a harmonized processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find that regional molecular vulnerability and macroscale brain network architecture interact to drive the spatial patterning of cortical abnormalities in multiple disorders. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, medial temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local biological attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

neuroscience↗

bioRxiv2021

Gestational methylazoxymethanol acetate administration alters α5GABAA and NMDA receptor density: An integrated neuroimaging, behavioral and pharmacological study

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in dorsal hippocampus CA1, ventral hippocampus CA1, and in ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of 5 GABAA receptors (5GABAAR), [3H]-flumazenil to quantify 1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. 5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-Flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of 5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

neuroscience↗

bioRxiv2021

Cellular and molecular signatures of in vivo GABAergic neurotransmission in the human brain

Diverse GABAergic interneuron microcircuits orchestrate information processing in the brain. Understanding the cellular and molecular composition of these microcircuits, and whether these can be imaged by available non-invasive in vivo methods is crucial for the study of GABAergic neurotransmission in health and disease. Here, we use human gene expression data and state-of-the-art imaging transcriptomics to uncover co-expression patterns between GABAA receptor subunits and interneuron subtype-specific markers, and to decode the cellular and molecular signatures of gold-standard GABA PET radiotracers, [11C]Ro15-4513 and [11C]flumazenil. We find that the interneuron marker somatostatin is co-expressed with GABAA receptor-subunit genes GABRA5 and GABRA2, and their distribution maps onto [11C]Ro15-4513 binding in vivo. In contrast, the interneuron marker parvalbumin co-expressed with more predominant GABAA receptor subunits (GABRA1, GABRB2 and GABRG2), and their distribution tracks [11C]flumazenil binding in vivo. These results have important implications for the non-invasive study of GABAergic microcircuit dysfunction in psychiatric conditions.

neuroscience↗

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↗