2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Down-Syndrome

Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABA. To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice.. We now show that GABA. It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABA

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Down Syndrome; Electroencephalography; Embryo, Mammalian; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Genotype; Hippocampus; Humans; In Vitro Techniques; Infant; Membrane Potentials; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Peptide Hydrolases; Quinoxalines; Sodium Oxybate; Spasms, Infantile; Trisomy

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cognition Disorders; Crosses, Genetic; Dentate Gyrus; Disease Models, Animal; Down Syndrome; Evoked Potentials; Female; GABA-A Receptor Antagonists; Gene Dosage; Glycine; Hippocampus; Long-Term Potentiation; Magnesium; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Mutant Strains; Patch-Clamp Techniques; Picrotoxin; Presynaptic Terminals; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Species Specificity; Trisomy

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