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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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

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

Fingerprint

Dive into the research topics of 'Neuronal Glud1 (glutamate dehydrogenase 1) over-expressing mice: Increased glutamate formation and synaptic release, loss of synaptic activity, and adaptive changes in genomic expression'. Together they form a unique fingerprint.

Cite this