GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study

Paulina Lukow; Julia Schubert; Mario Severino; Samuel Knight; Amanda Kiemes; Nicholas Livingston; James Davies; Andrea De Micheli; Tom Spencer; Paolo Fusar-Poli; Beate Haege; Natasha Vorontsova; Jacek Donocik; Eugenii Rabiner; Anthony A. Grace; Steven Williams; Philip McGuire; Mattia Veronese; Federico Turkheimer; Gemma Modinos

GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study

Paulina Lukow, Julia Schubert, Mario Severino, Samuel Knight, Amanda Kiemes, Nicholas Livingston, James Davies, Andrea De Micheli, Tom Spencer, Paolo Fusar-Poli, Beate Haege, Natasha Vorontsova, Jacek Donocik, Eugenii Rabiner, Anthony A. Grace, Steven Williams, Philip McGuire, Mattia Veronese, Federico Turkheimer, Gemma Modinos

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Abstract

Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAA receptors containing the α5 subunit (GABAARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50)=0.25, p=0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p<0.001, pairwise Cohen’s d = 0.07-0.5) and relative to the hippocampus (all p<0.001, pairwise Cohen’s d = 0.01-0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level.

Original language	English
Journal	Molecular Psychiatry
Publication status	Accepted/In press - 5 Jun 2025

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Main manuscript_revisedAccepted author manuscript, 970 KBLicence: CC BY

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Lukow, P., Schubert, J., Severino, M., Knight, S., Kiemes, A., Livingston, N., Davies, J., De Micheli, A., Spencer, T., Fusar-Poli, P., Haege, B., Vorontsova, N., Donocik, J., Rabiner, E., Grace, A. A., Williams, S., McGuire, P., Veronese, M., Turkheimer, F., & Modinos, G. (Accepted/In press). GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study. Molecular Psychiatry.

@article{55220d2857664120a5904bd479391b41,

title = "GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study",

abstract = "Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAA receptors containing the α5 subunit (GABAARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50)=0.25, p=0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p<0.001, pairwise Cohen{\textquoteright}s d = 0.07-0.5) and relative to the hippocampus (all p<0.001, pairwise Cohen{\textquoteright}s d = 0.01-0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level. ",

author = "Paulina Lukow and Julia Schubert and Mario Severino and Samuel Knight and Amanda Kiemes and Nicholas Livingston and James Davies and {De Micheli}, Andrea and Tom Spencer and Paolo Fusar-Poli and Beate Haege and Natasha Vorontsova and Jacek Donocik and Eugenii Rabiner and Grace, {Anthony A.} and Steven Williams and Philip McGuire and Mattia Veronese and Federico Turkheimer and Gemma Modinos",

year = "2025",

month = jun,

day = "5",

language = "English",

journal = "Molecular Psychiatry",

issn = "1476-5578",

publisher = "Springer Nature [academic journals on nature.com]",

}

Lukow, P , Schubert, J, Severino, M, Knight, S , Kiemes, A , Livingston, N, Davies, J, De Micheli, A , Spencer, T , Fusar-Poli, P, Haege, B, Vorontsova, N , Donocik, J , Rabiner, E, Grace, AA, Williams, S , McGuire, P, Veronese, M, Turkheimer, F & Modinos, G 2025, 'GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study', Molecular Psychiatry.

TY - JOUR

T1 - GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study

AU - Lukow, Paulina

AU - Schubert, Julia

AU - Severino, Mario

AU - Knight, Samuel

AU - Kiemes, Amanda

AU - Livingston, Nicholas

AU - Davies, James

AU - De Micheli, Andrea

AU - Spencer, Tom

AU - Fusar-Poli, Paolo

AU - Haege, Beate

AU - Vorontsova, Natasha

AU - Donocik, Jacek

AU - Rabiner, Eugenii

AU - Grace, Anthony A.

AU - Williams, Steven

AU - McGuire, Philip

AU - Veronese, Mattia

AU - Turkheimer, Federico

AU - Modinos, Gemma

PY - 2025/6/5

Y1 - 2025/6/5

N2 - Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAA receptors containing the α5 subunit (GABAARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50)=0.25, p=0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p<0.001, pairwise Cohen’s d = 0.07-0.5) and relative to the hippocampus (all p<0.001, pairwise Cohen’s d = 0.01-0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level.

AB - Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAA receptors containing the α5 subunit (GABAARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50)=0.25, p=0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p<0.001, pairwise Cohen’s d = 0.07-0.5) and relative to the hippocampus (all p<0.001, pairwise Cohen’s d = 0.01-0.67). These findings suggest that individuals at clinical high-risk for psychosis and people with early psychosis may show alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level.

M3 - Article

SN - 1476-5578

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

GABAA receptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study

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