Neuronal Glud1 (glutamate dehydrogenase 1) over-expressing mice: Increased glutamate formation and synaptic release, loss of synaptic activity, and adaptive changes in genomic expression

E. K. Michaelis, X. Wang, R. Pal, X. Bao, K. N. Hascup, Y. Wang, W. T. Wang, D. Hui, A. Agbas, I. Y. Choi, A. Belousov, G. A. Gerhardt

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Glutamate dehydrogenase 1 (GLUD1) is a mitochondrial enzyme expressed in all tissues, including brain. Although this enzyme is expressed in glutamatergic pathways, its function as a regulator of glutamate neurotransmitter levels is still not well defined. In order to gain an understanding of the role of GLUD1 in the control of glutamate levels and synaptic release in mammalian brain, we generated transgenic (Tg) mice that over-express this enzyme in neurons of the central nervous system. The Tg mice have increased activity of GLUD, as well as elevated levels and increased synaptic and depolarization-induced release of glutamate. These mice suffer age-associated losses of dendritic spines, nerve terminals, and neurons. The neuronal losses and dendrite structural changes occur in select regions of the brain. At the transcriptional level in the hippocampus, cells respond by increasing the expression of genes related to neurite growth and synapse formation, indications of adaptive or compensatory responses to the effects of increases in the release and action of glutamate at synapses. Because these Tg mice live to a relatively old age they are a good model of the effects of a "hyperglutamatergic" state on the aging process in the nervous system. The mice are also useful in defining the molecular pathways affected by the over-activation of GLUD in glutamatergic neurons of the brain and spinal cord.

Original languageEnglish
Pages (from-to)473-481
Number of pages9
JournalNeurochemistry International
Volume59
Issue number4
DOIs
StatePublished - Sep 2011

Bibliographical note

Funding Information:
This work was funded by grants from NIA , AG12993 , NICHD , HD02528 , NIAAA AA11419 , AA04732 , AA12276 , NSF DBI-9987807 , DBI-0352848 , NIDA DA017186 , NINDS NS39787 , and NIMH MH58414 , NIDA Training Grant DA022738 , NIDA DA015088 , Kansas Technology Enterprise Corporation , the Miller, Hedwig and Wilbur fund, and the University of Kansas Research Development Fund . The support of the Higuchi Biosciences Center is acknowledged.

Funding

This work was funded by grants from NIA , AG12993 , NICHD , HD02528 , NIAAA AA11419 , AA04732 , AA12276 , NSF DBI-9987807 , DBI-0352848 , NIDA DA017186 , NINDS NS39787 , and NIMH MH58414 , NIDA Training Grant DA022738 , NIDA DA015088 , Kansas Technology Enterprise Corporation , the Miller, Hedwig and Wilbur fund, and the University of Kansas Research Development Fund . The support of the Higuchi Biosciences Center is acknowledged.

FundersFunder number
Kansas Technology Enterprise Corporation
National Science Foundation Arctic Social Science ProgramDBI-0352848, DBI-9987807
National Science Foundation Arctic Social Science Program
National Institute of Mental HealthDA015088, MH58414, DA022738
National Institute of Mental Health
National Institute on Drug Abuse or National Institute on Alcohol Abuse and AlcoholismDA017186
National Institute on Drug Abuse or National Institute on Alcohol Abuse and Alcoholism
National Institute on Alcohol Abuse and AlcoholismAA11419, AA12276, AA04732
National Institute on Alcohol Abuse and Alcoholism
National Institute on AgingAG12993
National Institute on Aging
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke CouncilP50NS039787
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
University of Kansas and University of Kansas Cancer Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research NetworkHD02528
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

    Keywords

    • Aging
    • Depolarization-induced glutamate release
    • Glutamate dehydrogenase
    • LTP
    • Spine loss
    • Synapse loss
    • Transcriptomic changes

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience
    • Cell Biology

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