In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients.
In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients.
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DOI：
10.1176/appi.ajp.2015.14081031
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发表时间：
2015-11-01
期刊：
影响因子：
--
通讯作者：
Narendran R
中科院分区：
文献类型：
--
作者：
Frankle WG;Cho RY;Prasad KM;Mason NS;Paris J;Himes ML;Walker C;Lewis DA;Narendran R
精神分裂症的尸检研究揭示了调节GABA释放和细胞外持久性的基因产物的改变。然而，在体内研究精神分裂症的磁共振波谱（MRS）测量总组织GABA的结果一直不一致。无论是尸检还是MRS研究都没有直接涉及GABA神经传递的生理特性。本研究通过一种创新的正电子发射断层扫描（PET）范式来解决这个问题。[11 C]氟马西尼，苯二氮卓类特异性PET放射性示踪剂的结合，测定之前和之后的噻加宾（0.2 mg/kg体重），GABA膜转运蛋白（GAT 1）阻滞剂，在17个停药的精神分裂症患者和22名健康对照受试者。通过GAT 1阻断，细胞外GABA增加，增强了GABAA受体对苯二氮卓类配体的亲和力，检测为[11 C]氟马西尼组织分布体积（VT）增加。[11 C]氟马西尼VT在健康对照组的所有皮质脑区域均显著增加，但在精神分裂症组中没有。这种效果的缺乏在抗精神病药物初治的精神分裂症组中最为突出。在该亚组中，内侧颞叶的[11 C]氟马西尼ΔVT与阳性症状相关，内侧颞叶的基线[11 C]氟马西尼VT与视觉学习呈负相关。在健康对照组而非精神分裂症组中，[11 C]氟马西尼ΔVT与γ波段振荡功率呈正相关。这项研究表明，第一次，在精神分裂症的GABA传输体内损伤，最突出的抗精神病药初治个体。GABA传递的损伤似乎与临床症状、皮质振荡紊乱和认知有关。
Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. The binding of [11C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [11C]flumazenil tissue distribution volume (VT). [11C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [11C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [11C] flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [11C]flumazenil ΔVT was positively associated with gamma-band oscillation power. This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.
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