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 alpha 5 subtype of the GABA receptor (alpha 5-GABA(A)Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal alpha 5-GABA(A)Rs protein and mRNA levels in schizophrenia. However, it is unclear if alpha 5-GABA(A)Rs are altered in vivo or related to symptoms. We investigated alpha 5-GABA(A)Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [C-11]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 [C-11]Ro15-4513 PET scan and MRI. The alpha 5 subtype GABA-A receptor availability was indexed using [C-11]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 [C-11]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 alpha 5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

Automated summary

The study showed that antipsychotic-free schizophrenia patients have lower levels of alpha 5-GABA(A)Rs in the hippocampus, and there is a significant positive correlation between the levels and PANSS score in these patients.