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Open Access Highly Accessed Research article

Gene expression patterns in the hippocampus during the development and aging of Glud1 (Glutamate Dehydrogenase 1) transgenic and wild type mice

Xinkun Wang123*, Nilam D Patel1, Dongwei Hui13, Ranu Pal13, Mohamed M Hafez4, Mohamed M Sayed-Ahmed4, Abdulaziz A Al-Yahya45 and Elias K Michaelis123

Author Affiliations

1 Higuchi Biosciences Center, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA

2 Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, KS 66160, USA

3 Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA

4 Department of Pharmacology and Toxicology, School of Pharmacy, King Saud University, Riyadh, Saudi Arabia

5 Ibn Sina National College, Jeddah, Saudi Arabia

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BMC Neuroscience 2014, 15:37  doi:10.1186/1471-2202-15-37

Published: 4 March 2014

Abstract

Background

Extraneuronal levels of the neurotransmitter glutamate in brain rise during aging. This is thought to lead to synaptic dysfunction and neuronal injury or death. To study the effects of glutamate hyperactivity in brain, we created transgenic (Tg) mice in which the gene for glutamate dehydrogenase (Glud1) is over-expressed in neurons and in which such overexpression leads to excess synaptic release of glutamate. In this study, we analyzed whole genome expression in the hippocampus, a region important for learning and memory, of 10 day to 20 month old Glud1 and wild type (wt) mice.

Results

During development, maturation and aging, both Tg and wt exhibited decreases in the expression of genes related to neurogenesis, neuronal migration, growth, and process elongation, and increases in genes related to neuro-inflammation, voltage-gated channel activity, and regulation of synaptic transmission. Categories of genes that were differentially expressed in Tg vs. wt during development were: synaptic function, cytoskeleton, protein ubiquitination, and mitochondria; and, those differentially expressed during aging were: synaptic function, vesicle transport, calcium signaling, protein kinase activity, cytoskeleton, neuron projection, mitochondria, and protein ubiquitination. Overall, the effects of Glud1 overexpression on the hippocampus transcriptome were greater in the mature and aged than the young.

Conclusions

Glutamate hyperactivity caused gene expression changes in the hippocampus at all ages. Some of these changes may result in premature brain aging. The identification of these genomic expression differences is important in understanding the effects of glutamate dysregulation on neuronal function during aging or in neurodegenerative diseases.

Keywords:
Brain aging; Hippocampus; Glutamate; Gene expression profile; Genome