2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Alzheimer-Disease

Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing.

Topics: 4-Aminopyridine; Action Potentials; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cortical Synchronization; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Long-Term Potentiation; Mice; Mice, Transgenic; Mutation; Nerve Net; Neural Inhibition; Neural Pathways; Organ Culture Techniques; Potassium Channel Blockers; Presynaptic Terminals; Quinoxalines; Synaptic Transmission

It has been suggested that augmented nerve cell death in neurodegenerative diseases might result from an impairment of mitochondrial function. To test this hypothesis, we investigated age-dependent changes in neuronal survival and glutamate effects on Ca2+ homeostasis and mitochondrial energy metabolism in cultured hippocampal neurons from diploid and trisomy 16 (Ts16) mice, a model of Down's syndrome. Microfluorometric techniques were used to measure survival rate, [Ca2+]i level, mitochondrial membrane potential, and NAD(P)H autofluorescence. We found that Ts16 neurons die more than twice as fast as diploid neurons under otherwise identical culture conditions. Basal [Ca2+]i levels were elevated in Ts16 neurons. Moreover, in comparison to diploid neurons, Ts16 neurons showed a prolonged recovery of [Ca2+]i and mitochondrial membrane potential after brief glutamate application. Glutamate evoked an initial NAD(P)H decrease that was found to be extended in Ts16 neurons in comparison to diploid neurons. Furthermore, for all age groups tested, glutamate failed to cause a subsequent NAD(P)H overshoot in Ts16 cultures in contrast to diploid cultures. In the presence of cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition, NAD(P)H increase was observed in both diploid and Ts16 neurons. The results support the hypothesis that Ca2+ impairs mitochondrial energy metabolism and may play a role in the pathogenesis of neurodegenerative changes in neurons from Ts16 mice.

Topics: Aging; Alzheimer Disease; Animals; Calcium; Carcinogens; Cell Death; Cyclosporine; Diploidy; Disease Models, Animal; Down Syndrome; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Hippocampus; Karyotyping; Male; Membrane Potentials; Mice; Mice, Neurologic Mutants; Mitochondria; NADP; Neurons; Potassium; Quinoxalines; Signal Transduction; Trisomy; Vitamin E