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

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_ARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA_ARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA_ARs are altered in vivo or related to symptoms. We investigated α5-GABA_ARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [¹¹C]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 [¹¹C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [¹¹C]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 [¹¹C]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.