Mouse Genome Informatics
cx
    Tg(GFAP-tTA)#Hyms/0
Tg(tetO-HMOX1)#Hyms/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
behavior/neurological
• mutants exhibit increased locomotor activity in an open-field test at 48 weeks compared to controls
• however, no differences in rotoarod or anxiety tests are seen compared to controls

nervous system
• astroglia from amygdala and substantia nigra exhibit accumulation of iron-laden intracellular inclusions (J:186620)
• numbers of ferric iron deposits are increased in the substantia nigra, ventral tegmental area, amygdala, entorhinal cortex, and ventral and dorsal hippocampus at 48 weeks of age (J:190573)
• ferric iron deposits are localized to astroglia, in degenerate organelles and osmiophilic cytoplasmic inclusions (J:190573)
• substantia nigra shows increased levels of dopamine and an increased trend of DOPAC
• striatum shows increased levels of dopamine, 5-HT and its metabolite 5-HIAA, and an increased trend of homovanilic acid
• hippocampal cytoarchitecture is altered
• the dorsal hippocampus is diminished at 48 weeks of age
• dysgenesis and shortening of the blades of the dentate gyrus
• reduction of granule cell packing densities in the crest of the dentate gyrus
• astrocytes from amygdala and substantia nigra show frequent invaginations of the nuclear envelope which are rarely seen in wild-type mice and exhibit abnormal mitochondria (J:186620)
• astrocytes exhibit abundant pleiomoprhic, osmiophilic inclusions and lipofuscin granules, features of macroautophagy and show accumulation of iron-laden intracellular inclusions (J:186620)
• gallyas-positive (degenerate) neurites are abundant in 48 week old mutants but are rarely seen in controls (J:186620)
• degenerate membranes are seen within neurites in close proximity to astrocytes (J:186620)
• 12 week old mutants exhibit an impaired evoked cortical cerebral blood flow (CBF) response induced by whisker stimulation, indicating impaired neurovascular coupling
• elevations in dopamine levels in the striatum and substantia nigra
• elevations in DOPAC in striatum and an increased trend in substantia nigra
• DOPAC/dopamine ratio remains unchanged in mutants, indicating a normal neurotransmitter turnover rate
• prepulse inhibition is attenuated in males, but not females, at 48 weeks of age (J:186620)

cellular
• in the substantia nigra and amygdala, astrocytic mitochondria are reduced in number, often distended, and characterized by disorganized, damaged, or absent cristae, exaggerated intercristal spacing, diffuse or segmental membrane rupture, and foci of electron dense material (J:186620)
• mitochondrial membrane damage with diffuse or segmental membrane ruputure
• in the substantia nigra and amygdala, astrocytic mitochondria are characterized by disorganized, damaged, or absent cristae, exaggerated intercristal spacing, diffuse or segmental membrane rupture, and foci of electron dense material (J:186620)
• in the substantia nigra and amygdala
• astrocytes exhibit abundant pleiomoprhic, osmiophilic inclusions and lipofuscin granules, features of macroautophagy and mitophagy (J:186620)
• frequently ferric iron colocalizes with elemental oxygen and sulfur, indicating that the autophagic material originates from the mitochondria and thus the presence of macroautophagy (J:190573)
• marker analysis indicates oxidative stress in the striatum at 6 weeks of age and in the striatum and substantia nigra-ventral tagmental area at 48 weeks of age (J:186620)
• mitochondrial oxidative stress in neurons and astrocytes of the substantia nigra (J:190573)

homeostasis/metabolism
• elevations in dopamine levels in the striatum and substantia nigra
• elevations in DOPAC in striatum and an increased trend in substantia nigra
• DOPAC/dopamine ratio remains unchanged in mutants, indicating a normal neurotransmitter turnover rate
• increase in 5-HT and its metabolite, 5-HIAA, in the striatum, but not other regions
• however, norepinephrine, epinephrine, GABA and glutamate levels are normal
• astroglia from amygdala and substantia nigra exhibit accumulation of iron-laden intracellular inclusions (J:186620)
• numbers of ferric iron deposits are increased in the substantia nigra, ventral tegmental area, amygdala, entorhinal cortex, and ventral and dorsal hippocampus at 48 weeks of age (J:190573)
• ferric iron deposits are localized to astroglia, in degenerate organelles and osmiophilic cytoplasmic inclusions (J:190573)

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:190573
Parkinson Disease, Late-Onset; PD 168600 J:190573
Schizophrenia; SCZD 181500 J:186620