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