Transgenic Expression ofGlud1(Glutamate Dehydrogenase 1) in Neurons:In VivoModel of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability

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.

Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

“…The transcriptomic data reported here on the up-regulation of protein ubiquitination genes matched our previous observations of large accumulations of ubiquitinated proteins in neurons of the same region in older Glud1 mice [14]. It should be noted that in this study, the transcriptional up-regulation of protein ubiquitination genes occurred by nine months of age, that is, it preceded the accumulation and aggregation of ubiquitinated proteins (not observed until the Tg mice were at sixteen months of age [14]).…”

“…It should be noted that in this study, the transcriptional up-regulation of protein ubiquitination genes occurred by nine months of age, that is, it preceded the accumulation and aggregation of ubiquitinated proteins (not observed until the Tg mice were at sixteen months of age [14]).…”

Selective Neuronal Vulnerability of Human Hippocampal CA1 Neurons: Lesion Evolution, Temporal Course, and Pattern of Hippocampal Damage in Diffusion-Weighted MR Imaging

“…27 As a consequence of altered ATP supplies, changes in ion gradients lead to the accumulation of extracellular glutamate, and the resulting intracellular accumulation of Ca 2+ results in cytotoxicity. 28 Oxidative stress is the result of an imbalance between the generation of deleterious reactive oxygen and nitrogen species and the cell's compensatory mechanisms. 28 The differential regional vulnerability of cerebral structures is at least partly also a reflection of regional differences in antioxidant enzymes.…”

“…28 Oxidative stress is the result of an imbalance between the generation of deleterious reactive oxygen and nitrogen species and the cell's compensatory mechanisms. 28 The differential regional vulnerability of cerebral structures is at least partly also a reflection of regional differences in antioxidant enzymes. 5,29 A common finding in these cases is the unilateral or bilateral involvement of the hippocampus.…”

Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State

“…In addition, patients harboring these mutations suffer from seizures that may be independent from their hypoglycaemic episodes (19). These observations, taken together with recent findings showing that overexpression of GDH1 in mice results in age-dependent degenerative changes in the CA1 region of the hippocampus (34), suggest that a tight regulation of GDH activity is of importance for nerve tissue function and degeneration. Regarding deregulation of hGDH2 in human disorders, recent studies revealed that patients with Parkinson disease, who were hemizygous for T1492G polymorphism in the GLUD2 gene, experienced onset of their disease 8 -13 years earlier than patients with other genotypes in two populations of diverse genetic background (35).…”