GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513

Abstract

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA A Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA A Rs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA A Rs are altered in vivo or related to symptoms. We investigated α5-GABA A Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [ 11 C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [ 11 C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [ 11 C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (V T ) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C] Ro15-4513 V T in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [ 11 C]Ro15-4513 V T and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

“…Of note, these data were collected in naïve animals, lacking any features relevant to the pathophysiology of schizophrenia. In this context, a recent PET study reported reduced [ 11 C]-Ro15–4513 V T in the hippocampus of antipsychotic-naïve schizophrenia patients, whilst no group differences were found in a second cohort of patients who were taking antipsychotics ( Marques et al., 2020 ). One interpretation of these data is that antipsychotics may have a “normalizing” effect and it is tempting to speculate that this is consistent with the increases seen in GABA A R availability herein.…”

“…Furthermore, to date, no studies have examined the potential impact of antipsychotic drug exposure using radioligands with greater selectivity for GABA A -BZR containing α1/α5 subunits, such as Ro15-4513 ( Lingford-hughes et al., 2002 ; Maeda et al., 2003 ). This is of clinical relevance, as a recent PET study in schizophrenia found reduced volume of distribution (V T ) of [ 11 C]- Ro15–4513 relative to healthy controls only in antipsychotic-naïve schizophrenia patients, whilst no group differences were found in antipsychotic-medicated schizophrenia patients relative to healthy controls ( Marques et al., 2020 ). Furthermore, convergent lines of evidence from animal models strongly suggest that allosteric modulators of α5GABA A R have potential as novel, non-dopaminergic antipsychotic compounds, by balancing hippocampal excitation via tonic inhibition of pyramidal neurons ( Bonin et al., 2007 ; Caraiscos et al., 2004 ; Donegan et al., 2019 ; Gerdjikov et al., 2008 ; Gill et al., 2011 ; Hauser et al., 2005 ; Semyanov et al., 2004 ; Towers et al., 2004 ).…”

Population-level variation of enhancer expression identifies novel disease mechanisms in the human brain

“…The α5-containing GABA-A receptor represents less than 5 percent of all GABA-A receptors and has a restricted distribution within the prefrontal cortex, hippocampus, and amygdala (Gill and Grace, 2014). Abnormalities in the GABA-A receptor have been observed extensively in SCZ (Marques et al, 2020; Rudolph and Möhler, 2014) and allosteric modulation of the α5-containing GABA-A receptor has been proposed to have the potential to ameliorate cognitive deficits in SCZ (Gill and Grace, 2014).…”

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-Flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

“…Furthermore, to date, no studies have examined the potential impact of antipsychotic drug exposure using radioligands with greater selectivity for GABA A -BZR containing α1/α5 subunits, such as Ro15-4513 (Lingford-hughes et al, 2002;Maeda et al, 2003). This is of clinical relevance, as a recent PET study in schizophrenia found reduced volume of distribution (V T ) of [ 11 C]-Ro15-4513 relative to healthy controls only in antipsychotic-naïve schizophrenia patients, whilst no group differences were found in antipsychotic-medicated schizophrenia patients relative to healthy controls (Marques et al, 2020). Furthermore, convergent lines of evidence from animal models strongly suggest that allosteric modulators of α5GABA A R have potential as novel, non-dopaminergic antipsychotic compounds, by balancing hippocampal excitation via tonic inhibition of pyramidal neurons (Bonin et al, 2007;Caraiscos et al, 2004;Donegan et al, 2019;Gerdjikov et al, 2008;Gill et al, 2011;Hauser et al, 2005;Semyanov et al, 2004;Towers et al, 2004).…”