Transgenic expression of Glud1 (glutamate dehydrogenase 1) in neurons: in vivo model of enhanced glutamate release, altered synaptic plasticity, and selective neuronal vulnerability.
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.
Bao
Xiaodong
X
Higuchi Biosciences Center, Department of Pharmacology and Toxicology, and Life Span Studies Institute, University of Kansas, Lawrence, KS 66047, USA.
Pal
Ranu
R
Hascup
Kevin N
KN
Wang
Yongfu
Y
Wang
Wen-Tung
WT
Xu
Wenhao
W
Hui
Dongwei
D
Agbas
Abdulbaki
A
Wang
Xinkun
X
Michaelis
Mary L
ML
Choi
In-Young
IY
Belousov
Andrei B
AB
Gerhardt
Greg A
GA
Michaelis
Elias K
EK
D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005969:Glutamate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*
D018698:Glutamic Acid; D005969:Glutamate Dehydrogenase