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Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability
Bao, Xiaodong Pal, Ranu Hascup, Kevin N. Wang, Yongfu Wang, Wen-Tung Xu, Wenhao Hui, Dongwei Agbas, Abdulbaki Wang, Xinkun Michaelis, Mary Lou
Bao, Xiaodong
Pal, Ranu
Hascup, Kevin N.
Wang, Yongfu
Wang, Wen-Tung
Xu, Wenhao
Hui, Dongwei
Agbas, Abdulbaki
Wang, Xinkun
Michaelis, Mary Lou
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Abstract
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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This is the published version. Copyright 2009 Society for Neuroscience.
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2009-11-04
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Society for Neuroscience
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Bao, X., R. Pal, K. N. Hascup, Y. Wang, W.-T. Wang, W. Xu, D. Hui, A. Agbas, X. Wang, M. L. Michaelis, I.-Y. Choi, A. B. Belousov, G. A. Gerhardt, and E. K. Michaelis. "Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability." Journal of Neuroscience 29.44 (2009): 13929-3944. http://dx.doi.org/10.1523/JNEUROSCI.4413-09.2009.