Imaging the “GABA Shift” in Schizophrenia

Abstract

A core pathology in schizophrenia is the imbalance in inhibition and excitation in cortical circuits related to alterations in the inhibitory neurotransmitter g-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate, resulting in suboptimal synchronization of neural circuits needed for cognitive function (1). Postmortem studies have provided definitive evidence for abnormal GABA-related parameters in schizophrenia, which are thought to reflect deficits inGABAtransmission,eitherasaprimaryorasecondary adjustment to alterations in glutamate.MRspectroscopy (MRS) measurements have provided discrepant results, indicating the possible effects of antipsychotic medications, as well as age, illness phase, and use of anticonvulsants, on measurements of GABA (2). One limitation of this literature is the absence of in vivo measures of GABA transmission in the vicinity of the synapse, which can only be provided by molecular positron emission tomography (PET) imaging. The ambitious study that Frankle and colleagues report in this issue (3) is an important first step in addressing this deficiency. Frankle et al. combined a few technical maneuvers to obtain their novelmeasureof in vivoperisynapticGABA tone. They used PET radiotracer imaging of the benzodiazepine site on the ionotropic GABAA receptor, with the radiotracer [C]flumazenil, which binds to all alpha subunit-containing GABAAreceptors, thustargetingsynapticaswellasextrasynaptic sites corresponding to the locationof theseGABAAreceptors (4). They combined imagingwith a pharmacological challenge using tiagabine, an inhibitor of the GABA transporter GAT1, to raise GABA levels acutely in the brain in areas where GAT1 is distributed, which include neuronal and glial sites. By imaging the benzodiazepine receptor before and after this intervention, the authorswere able to indirectly assess themagnitudeof change in GABA levels. The change in GABA tone induces a positive allosteric effect on the binding of the radiotracer to the benzodiazepine receptor, called the “GABA shift,” by enhancing the affinity of the receptor, measured here in the postchallenge conditionwithanincreaseinthedistributionvolume(VT)of[ C] flumazenil. Themagnitude of increase inVT (DVT) is an indirect index of the availability of synaptic GABA neurotransmission in the vicinity of the benzodiazepine receptor. This positive modulation suggests that [C]flumazenil may be acting in vivo as a partial agonist in this study. Negative modulation has been reported for inverse agonists. The authors provided validation for this method in earlier work by showing a relationship between GAT1 inhibition, achieved by administering different doses of tiagabine, and increases in GABA levels (5, 6). As opposed toMRSmeasures of GABA, which report on whole-tissue GABA levels, this method is unique in providing measures of GABA in the synaptic space. This is a great advance in the use of PET imaging to probeneurotransmission, and thefirst such report for the GABA-ergic system in schizophrenia. In this study, tiagabine produced a detectable and statistically significant effect in healthy control subjects and in patients with schizophrenia who had past exposure to antipsychotics but were currently antipsychotic free, but not in antipsychotic-naivepatients.Furthermore, antipsychotic-naive patients showed higher baseline VT compared with the other two groups. The authors conclude that low levels of GABA lead to blunting of the effect of tiagabine in antipsychotic-naive patients and to up-regulation of receptors as a potential compensatorymechanism.DVTwas related to gamma power inhealthycontrolsubjects but not in patients. Furthermore, antipsychoticnaive subjects showed a positive relationship between baseline VT and gamma power, indicating that up-regulation of benzodiazepine sites may be compensating to somedegree for the deficits in gammapower but not to the extent of improving cognition in general. The interpretation of the findings offered by the authors may seem, on the surface, to conflict with the concept of GABA shift onwhich this PETmethod is based, inwhich low GABA levels should lower affinity of the receptor for the tracer and result in low baseline VT. However, it is likely that while the affinity may decrease acutely, chronically the receptordensitywould increase, and thecombinationof change in affinity and density could lead to an overall increase in binding of the tracer at baseline. This up-regulation suggests that the GABAA receptor density is also increased, since the benzodiazepine receptor is a site on the GABAA receptor. This first report warrants cautious optimism. Caution is needed because of the relatively small sizes of the patient groups (eight antipsychotic-naive and nine antipsychoticfree patients). Differences between antipsychotic-free and antipsychotic-naive patients here may be a sampling artifact and not necessarily related to priormedication status per se, especially in the absence of a clear relationship between The authors conclude that low levels of GABA lead to blunting of the effect of tiagabine in antipsychoticnaive patients and to upregulation of receptors as a potential compensatory mechanism.