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Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory.
Genes, Brain and Behavior ( IF 2.5 ) Pub Date : 2020-01-03 , DOI: 10.1111/gbb.12636
Sharon Sima Lander 1 , Sergiy Chornyy 1 , Hazem Safory 2 , Amit Gross 1 , Herman Wolosker 2 , Inna Gaisler-Salomon 1
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Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS‐Glud1 −/− mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l ‐serine and d ‐serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal‐prefrontal cortex circuitry. Finally, hippocampus‐dependent contextual fear retrieval was deficient in CNS‐Glud1 −/− mice, and c‐Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion‐dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal‐prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity‐induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.

中文翻译:

谷氨酸脱氢酶缺乏会破坏海马和前额叶皮层的谷氨酸稳态,并损害识别记忆。

啮齿动物中的Glud1基因编码的谷氨酸脱氢酶1(GDH)是一种线粒体酶,对于维持三重突触处的谷氨酸稳态至关重要。我们以前的研究表明,海马可能特别容易受到中枢神经系统(CNS)中GDH缺乏的影响。在这里,我们首先询问中枢神经系统中具有Glud1纯合缺失的小鼠(CNS‐ Glud1 -/-小鼠)是否在海马中表达不同水平的谷氨酸,并发现谷氨酸以及背侧和腹侧海马中的谷氨酰胺升高,而海马中的谷氨酰胺升高内侧前额叶皮层(mPFC)。l丝氨酸和d丝氨酸有助于谷氨酸的稳态和NMDA受体功能,在腹侧海马和mPFC中均增加,而在腹侧海马中则增加。腹侧海马中GABA合成酶谷氨酸脱羧酶(GAD)GAD67的蛋白质表达水平也降低。行为分析显示视觉,空间和社交新颖性识别能力不足,这需要完整的海马-前额叶皮层电路。最后,CNS- Glud1-/-缺乏海马依赖性情境恐惧恢复小鼠,此任务后立即降低了CA1锥体层中的c-Fos表达(指示神经元激活)。这些数据表明谷氨酸稳态和兴奋性/抑制性平衡受到海马区依赖的破坏,并支持海马-前额叶皮层连通性下降的行为缺陷。与我们以前的数据一起,这些发现还指出了这些小鼠的基础性和活动性海马异常的不同模式。总之,GDH有助于健康的海马和PFC功能。GDH功能紊乱与几种精神病和神经病有关。
更新日期:2020-01-03
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