Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Hippocampus. 2012 May;22(5):1027-39. doi: 10.1002/hipo.22014. Epub 2012 Mar 19.
Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity, mainly in CA1, and manifest behavioral and neurochemical phenotypes suggestive of schizophrenia resilience. To address the basis for the hippocampal hypoactivity, we examined synaptic plastic mechanisms and glutamate receptor expression. Although baseline synaptic strength was unaffected in Schaffer collateral inputs to CA1, we found that long-term potentiation was attenuated. In wild-type (WT) mice, GLS1 gene expression was highest in the hippocampus and cortex, where it was reduced by about 50% in GLS1 hets. In other brain regions with lower WT GLS1 gene expression, there were no genotypic reductions. In adult GLS1 hets, NMDA receptor NR1 subunit gene expression was reduced, but not AMPA receptor GluR1 subunit gene expression. In contrast, juvenile GLS1 hets showed no reductions in NR1 gene expression. In concert with this, adult GLS1 hets showed a deficit in hippocampal-dependent contextual fear conditioning, whereas juvenile GLS1 hets did not. These alterations in glutamatergic synaptic function may partly explain the hippocampal hypoactivity seen in the GLS1 hets. The maturity-onset reduction in NR1 gene expression and in contextual learning supports the premise that glutaminase inhibition in adulthood should prove therapeutic in schizophrenia.
谷氨酸酶缺乏型小鼠（GLS1 杂合子）由于谷氨酸的再循环减少，其海马体活动出现局部减少，主要在 CA1 区，并表现出类似于精神分裂症抗性的行为和神经化学表型。为了解决海马体活动不足的基础问题，我们检查了突触可塑性机制和谷氨酸受体表达。尽管 Schaffer 侧支传入到 CA1 的基线突触强度不受影响，但我们发现长时程增强作用减弱了。在野生型（WT）小鼠中，GLS1 基因表达在海马体和皮层中最高，在 GLS1 杂合子中降低了约 50%。在其他脑区 WT GLS1 基因表达较低的情况下，没有基因型减少。在成年 GLS1 杂合子中，NMDA 受体 NR1 亚基基因表达减少，但 AMPA 受体 GluR1 亚基基因表达没有减少。相比之下，幼年 GLS1 杂合子中 NR1 基因表达没有减少。与此一致的是，成年 GLS1 杂合子在海马体依赖性情景恐惧条件反射中表现出缺陷，而幼年 GLS1 杂合子则没有。这些谷氨酸能突触功能的改变可能部分解释了 GLS1 杂合子中所见的海马体活动不足。NR1 基因表达和情景学习的成熟发作减少支持了这样的前提，即成年期谷氨酸酶抑制应该在精神分裂症中具有治疗作用。
