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.

Chronic hyperglycemia could lead to cerebral metabolic alterations and CNS injury. However, findings of metabolic alterations in poorly managed diabetes in humans and animal models are rather inconsistent. We have characterized the cerebral metabolic consequences of untreated hyperglycemia from the onset to the chronic stage in a streptozotocin-induced rat model of diabetes. In vivo 1H magnetic resonance spectroscopy (MRS) was used to measure over 20 neurochemicals longitudinally. Upon the onset of hyperglycemia (acute state), increases in brain glucose levels were accompanied by increases in osmolytes and ketone bodies, all of which remained consistently high through the chronic state of over 10 weeks of hyperglycemia. Only after over 4 weeks of hyperglycemia, the levels of other neurochemicals including N-acetylaspartate and glutathione were significantly reduced and these alterations persisted into the chronic stage. However, glucose transport was not altered in chronic hyperglycemia of over 10 weeks. When glucose levels were acutely restored to euglycemia, some neurochemical changes were irreversible, indicating the impact of prolonged uncontrolled hyperglycemia on the CNS. Furthermore, progressive changes in neurochemical levels from control to acute and chronic conditions demonstrated the utility of 1H MRS as a noninvasive tool in monitoring the disease progression in diabetes.

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The efficacy of bifunctional peptide inhibitor (BPI) in preventing blood-brain barrier (BBB) breakdown during onset of experimental autoimmune encephalomyelitis (EAE) and suppression of the disease was evaluated in mice. The mechanism that defines how BPI prevents the disease was investigated by measuring the in vitro cytokine production of splenocytes. Peptides were injected 5 to 11 days prior to induction of EAE, and the severity of the disease was monitored by a standard clinical scoring protocol and change in body weight. The BBB breakdown in diseased and treated mice was compared to that in normal control mice by determining deposition of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) in the brain using magnetic resonance imaging (MRI). Mice treated with PLP-BPI showed no or low indication of EAE as well as normal increase in body weight. In contrast, mice treated with the control peptide or PBS showed a decrease in body weight and a high disease score. The diseased mice had high deposition of Gd-DTPA in the brain, indicating breakdown in the BBB. However, the deposition of Gd-DTPA in PLP-BPI-treated mice was similar to that in normal control mice. Thus, PLP-BPI can suppress EAE when administered as a peptide vaccine and maintain the integrity of the BBB.