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The Journal of Neuroscience, November 4, 2009, 29(44):13929-13944; doi:10.1523/JNEUROSCI.4413-09.2009

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Cellular/Molecular
Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability

Xiaodong Bao,^1,2 Ranu Pal,^1,2,3 Kevin N. Hascup,⁴ Yongfu Wang,⁵ Wen-Tung Wang,⁶ Wenhao Xu,⁸ Dongwei Hui,¹ Abdulbaki Agbas,^1,2 Xinkun Wang,^1,2,3 Mary L. Michaelis,^1,2 In-Young Choi,^5,6,7 Andrei B. Belousov,⁵ Greg A. Gerhardt,⁴ and Elias K. Michaelis^1,2,3

¹Higuchi Biosciences Center, ²Department of Pharmacology and Toxicology, and ³Life Span Studies Institute, University of Kansas, Lawrence, Kansas 66047, ⁴Anatomy and Neurobiology, Center for Microelectrode Technology, Morris K. Udall Parkinson's Disease Research Center of Excellence, University of Kentucky, College of Medicine, Lexington, Kentucky 40536, ⁵Department of Molecular and Integrative Physiology, ⁶Hoglund Brain Imaging Center, and ⁷Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66160, and ⁸Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908

Correspondence should be addressed to Dr. Elias K. Michaelis, Higuchi Biosciences Center, 2099 Constant Avenue, University of Kansas, Lawrence, KS 66047. Email: emichaelis{at}ku.edu

The effects of lifelong, moderate excess release of glutamate (Glu) in the CNS have not been previously characterized. We created a transgenic (Tg) mouse model of lifelong excess synaptic Glu release in the CNS by introducing the gene for glutamate dehydrogenase 1 (Glud1) under the control of the neuron-specific enolase promoter. Glud1 is, potentially, an important enzyme in the pathway of Glu synthesis in nerve terminals. Increased levels of GLUD protein and activity in CNS neurons of hemizygous Tg mice were associated with increases in the in vivo release of Glu after neuronal depolarization in striatum and in the frequency and amplitude of miniature EPSCs in the CA1 region of the hippocampus. Despite overexpression of Glud1 in all neurons of the CNS, the Tg mice suffered neuronal losses in select brain regions (e.g., the CA1 but not the CA3 region). In vulnerable regions, Tg mice had decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals; the decreases in neuronal numbers and dendrite and presynaptic terminal labeling increased with advancing age. In addition, the Tg mice exhibited decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Behaviorally, the Tg mice were significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission. The Glud1 mouse might be a useful model for the effects of lifelong excess synaptic Glu release on CNS neurons and for age-associated neurodegenerative processes.

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Received Sept. 7, 2009; accepted Sept. 28, 2009.

Correspondence should be addressed to Dr. Elias K. Michaelis, Higuchi Biosciences Center, 2099 Constant Avenue, University of Kansas, Lawrence, KS 66047. Email: emichaelis{at}ku.edu

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