Analysis Tools
mortality/aging
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• ~50% of homozygotes die spontaneously at 4 to 5 weeks of age; the remaining ~50% die at a rather constant rate until 13 weeks of age
• survival can be extended by an average of 4 weeks by oral administration of the antiepileptic drug DPA (3 mg/ml); however, epileptic attacks that are initially controlled by DPA become uncontrollable by 12 weeks of age
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nervous system
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• homozygotes die from grand mal-type epileptic attacks with jumping fits or refractory status epilepticus
• epileptic seizures include jumping fits, forelimb clonus, running fits, tonic-clonic seizures, and myoclonic jerks of the limbs and the trunk
• the frequency of epileptic seizures is significantly reduced until 7-8 weeks by oral administration of DPA
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• at 5 weeks, homozygotes show a proportional enlargement of the gray matter and white matter of the cerebral cortex, hippocampus, striatum, thalamus, and cerebellum; no significantly increased numbers of neurons, astrocytes or oligodendrocytes are observed
• mutant brain volume begins to increase after 4 weeks of age until it finally reaches an average of ~25% increase at ~10 weeks
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• homozygous mutant brains are 15% heavier than those of heterozygous mutant mice
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• homozygotes display aberrant cortical pyramidal neuron morphology, with an abnormally ballooned nucleus and a clearly demarcated nucleolus in layer V
• apical dendrites of mutant pyramidal neurons in layers II and III of the cerebral cortex display twisted configurations with abnormal winding and bifurcations in the proximal portion
• in addition, dendrites of mutant pyramidal neurons show disorganized microtubules with bundles being unevenly or peripherally localized inside the dendritic fibers
• pyramidal cells in layer III of the mutant cerebral cortex display a slight reduction in axon diameter
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• pyramidal cells in layer III of the mutant cerebral cortex display a slight reduction in axon diameter
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• homozygotes exhibit clinical convulsions with EEG recordings of paroxysmal cortical discharges
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homeostasis/metabolism
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• homozygotes display an increased blood urea nitrogen level relative to wild-type mice (30.3 vs 19.7 mg/dl)
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• homozygotes show increased levels of corticosterone relative to wild-type mice (0.24 vs 0.12 mg/ml)
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• homozygotes show normal levels of free T3 and T4 but increased levels of aldosterone relative to wild-type mice (830 vs 430 pg/ml)
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• homozygotes exhibit decreased levels of total cholesterol (86 vs 116 mg/dl) and esterified cholesterol (75 vs 105 mg/dl)
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• homozygotes show normal levels of phospholipid and free fatty acids but an increased level of triglycerides relative to wild-type mice (70 vs 52 mg/dl)
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• homozygotes show normal levels for Na, K, Cl, Ca, and creatinine but a reduced phosphate level relative to wild-type mice (9.8 vs 12.1 mg/dl)
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• homozygotes exhibit reduced levels of creatine phosphokinase relative to wild-type mice (1138 vs 2135 IU/l)
• in contrast, levels of total protein, albumin, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase, and cholinesterase remain normal
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• homozygotes exhibit reduced blood levels of lactate dehydrogenase relative to wild-type mice (996 vs 1306 IU/l, respectively)
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• homozygotes display reduced ferritin levels relative to wild-type mice (2.5 vs 5.2 ng/ml)
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behavior/neurological
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• homozygotes die from grand mal-type epileptic attacks with jumping fits or refractory status epilepticus
• epileptic seizures include jumping fits, forelimb clonus, running fits, tonic-clonic seizures, and myoclonic jerks of the limbs and the trunk
• the frequency of epileptic seizures is significantly reduced until 7-8 weeks by oral administration of DPA
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growth/size/body
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• homozygotes display a ~35% decrease in body weight until 7 weeks after birth
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hematopoietic system
small spleen
(
J:46228
)
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• homozygous mutant spleens are 28% smaller than those of heterozygous mutant mice
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skeleton
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• ~20% of homozygotes display kyphosis of the spine, with no abnormalities found in the bones of vertebrae, skulls, or limbs
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immune system
small spleen
(
J:46228
)
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• homozygous mutant spleens are 28% smaller than those of heterozygous mutant mice
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muscle
respiratory system
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• homozygotes exhibit respiratory arrests after grand mal attacks
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cellular
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• homozygotes exhibit significant accumulation of L-isoaspartyl residues in the brain, testis, heart, muscle, spleen, and eyes
• in contrast, D-aspartate residues appear to be slightly decreased in mutant brain
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