Analysis Tools
mortality/aging
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• ~30-40% of homozygotes die in the first postnatal week because of diabetes
• Background Sensitivity: when heterozygotes of a hybrid (129/SvEv x C57BL/6J) genetic background are crossed into the 129X1/SvJ background, about 60-70% of homozygotes survive to adulthood
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behavior/neurological
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• adult homozygotes exhibit swaying head movements
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hyperactivity
(
J:59932
)
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• adult homozygotes display hyperactivity
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• homozygotes display a seizure disorder with both limbic and generalized features
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• generalized tonic-clonic seizures occur occasionally, accompanied by either sustained cortical epileptiform discharges or intermittent abnormal synchronous discharges
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• adult homozygotes display frequent (1-3 episodes/hour) spontaneous behavioral seizures that resemble those seen in models of limbic epilepsy
• typical episodes are brief (5-15 sec) with sudden focal dystonic posturing, flexor spasm of one or both forelimbs, and versive head movements
• episodic, brief freezing spells with tonic posturing are exacerbated by handling
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nervous system
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• homozygotes display a seizure disorder with both limbic and generalized features
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• generalized tonic-clonic seizures occur occasionally, accompanied by either sustained cortical epileptiform discharges or intermittent abnormal synchronous discharges
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• adult homozygotes display frequent (1-3 episodes/hour) spontaneous behavioral seizures that resemble those seen in models of limbic epilepsy
• typical episodes are brief (5-15 sec) with sudden focal dystonic posturing, flexor spasm of one or both forelimbs, and versive head movements
• episodic, brief freezing spells with tonic posturing are exacerbated by handling
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• homozygotes show striking defects in hippocampal formation
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• homozygotes show intact migration of mitotic precursor cells from the hippocampal neuroepithelium but fail to form the scaffolding of the dentate granule cell layer
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• homozygotes lack an organized dentate gyrus
• a small, disorganized dentate cap contains a rudimentary population of cells, just separated from the CA3 pyramidal region, with some features of dentate granule neurons and other cells that resemble hilar interneurons
• a progressive decline in the number of mitotic (BrdUrd-labeled) precursor cells is seen in the dentate gyrus region from E16.5 to P4
• at E18.5, the forming upper blade of the mutant dentate is underpopulated with precursor cells and newly born granule cells, indicating impaired formation of the initial scaffolding of the dentate gyrus
• excessive cell death is seen in the dentate gyrus from P2 to P14; however, the specific identity of dying cells remains elusive
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• homozygotes show no organized dentate hilus
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• homozygotes lack the dentate granule cell layer
• at P5, the dentate gyrus consists only of a small mass of cells expressing calbindin with no orderly granule cell layer, contains significanlty fewer mitotic cells, and shows a low level of Prox-1 expression confined to the abnormal dentate cap, suggesting that differentiation of granule-like cells is delayed
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• neurons born at the ventricular surface fail to express a specific dentate granule cell marker at the appropriate time during migration to the dentate gyrus
• at P5, differentiation of granule-like cells in the dentate cap appears to be delayed
• at P11, the tertiary matrix involutes and appears disorganized, similar to the abnormal structure present in adult mutant mice
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• homozygotes display cerebellar defects that result in ataxia
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• EEG activity during the spontaneous behavioral seizures consists of a stereotyped, rapid-burst discharge, followed by slower-interval synchronized spiking
• however, slow (theta) wave activity in the hippocampus remains normal
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homeostasis/metabolism
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• homozygotes that survive to adulthood show no ketonuria
• insulin levels return to normal values by 3 weeks of age
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hyperglycemia
(
J:59932
)
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• homozygotes that survive to adulthood are slightly hyperglycemic
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