University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, 1720 2nd Ave S., Birmingham, AL 35294, United States of America.
University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, 1720 2nd Ave S., Birmingham, AL 35294, United States of America.
Schizophr Res. 2022 Nov;249:16-24. doi: 10.1016/j.schres.2020.01.025. Epub 2020 Feb 1.
The glutamate hypothesis of schizophrenia suggests that altered glutamatergic transmission occurs in this illness, although precise mechanisms of dysregulation remain elusive. AMPA receptors (AMPARs), a subtype of ionotropic glutamate receptor, are the main facilitators of fast, excitatory neurotransmission in the brain, and changes in AMPAR number or composition at synapses can regulate synaptic strength and plasticity. Prior evidence of abnormal expression of transmembrane AMPAR regulatory proteins (TARPs) in schizophrenia suggests defective trafficking of AMPARs, which we propose could lead to altered AMPAR expression at excitatory synapses. To test this hypothesis, we isolated subcellular fractions enriched for endoplasmic reticulum (ER) and synapses from anterior cingulate cortex (ACC) from schizophrenia (N = 18) and comparison (N = 18) subjects, and measured glutamate receptor subunits (GluA1, GluA2, GluA3, GluA4, NR1, NR2A, NR2B, and NR3A) and TARP member γ2 (stargazin) in homogenates and subcellular fractions by western blot analysis. We found decreased expression of stargazin and an increased ratio of GluA2:stargazin in ACC homogenates, while in the synapse fraction we identified a decrease in GluA1 and reduced ratios of GluA1:stargazin and GluA1:GluA2 in schizophrenia. The amount of stargazin in the ER fraction was not different, but the relative amount of ER/Total stargazin was increased in schizophrenia. Together, these findings suggest that associations between stargazin and AMPA subunits are abnormal, potentially affecting forward trafficking or synaptic stability of GluA1-containing AMPARs. These data provide evidence that altered interactions with trafficking proteins may contribute to glutamate dysregulation in schizophrenia.
精神分裂症的谷氨酸假说表明，这种疾病存在谷氨酸能传递的改变，尽管确切的失调机制仍难以捉摸。AMPA 受体（AMPARs）是离子型谷氨酸受体的一种亚型，是大脑中快速兴奋性神经传递的主要促进剂，突触处 AMPAR 数量或组成的变化可以调节突触强度和可塑性。先前在精神分裂症中发现跨膜 AMPAR 调节蛋白（TARPs）异常表达的证据表明 AMPAR 的转运缺陷，我们提出这可能导致兴奋性突触处 AMPAR 表达的改变。为了验证这一假说，我们从精神分裂症（N=18）和对照组（N=18）受试者的前扣带皮层（ACC）中分离富含内质网（ER）和突触的亚细胞成分，并通过 Western blot 分析测量谷氨酸受体亚基（GluA1、GluA2、GluA3、GluA4、NR1、NR2A、NR2B 和 NR3A）和 TARP 成员 γ2（星型蛋白）在匀浆和亚细胞成分中的表达。我们发现 ACC 匀浆中星型蛋白表达减少，GluA2:星型蛋白的比值增加，而在突触部分，我们发现精神分裂症患者的 GluA1 减少，GluA1:星型蛋白和 GluA1:GluA2 的比值降低。ER 部分的星型蛋白含量没有差异，但精神分裂症患者的 ER/总星型蛋白的相对含量增加。总之，这些发现表明星型蛋白与 AMPA 亚基之间的关联异常，可能影响含 GluA1 的 AMPAR 的正向转运或突触稳定性。这些数据提供了证据表明，与转运蛋白的相互作用改变可能导致精神分裂症中谷氨酸能的失调。
