All Phenotypes Tg(tetO-HMOX1)6Hyms MGI Mouse

increased locomotor activity ( J:186620 )

• 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

increased brain iron level ( J:186620 , J:190573 )

• 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)

abnormal substantia nigra morphology ( J:186620 )

• substantia nigra shows increased levels of dopamine and an increased trend of DOPAC

abnormal striatum morphology ( J:186620 )

• striatum shows increased levels of dopamine, 5-HT and its metabolite 5-HIAA, and an increased trend of homovanilic acid

abnormal hippocampus morphology ( J:186620 )

• hippocampal cytoarchitecture is altered

• the dorsal hippocampus is diminished at 48 weeks of age

abnormal dentate gyrus morphology ( J:186620 )

• dysgenesis and shortening of the blades of the dentate gyrus

• reduction of granule cell packing densities in the crest of the dentate gyrus

abnormal astrocyte morphology ( J:186620 , J:190573 )

• 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)

abnormal neurite morphology ( J:186620 , J:190573 )

• 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)

abnormal nervous system physiology ( J:186620 )

• 12 week old mutants exhibit an impaired evoked cortical cerebral blood flow (CBF) response induced by whisker stimulation, indicating impaired neurovascular coupling

decreased prepulse inhibition ( J:186620 )

• prepulse inhibition is attenuated in males, but not females, at 48 weeks of age

abnormal mitochondrial morphology ( J:186620 , J:190573 )

• 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)

abnormal mitochondrial inner membrane morphology ( J:190573 )

• mitochondrial membrane damage with diffuse or segmental membrane ruputure

abnormal mitochondrial crista morphology ( J:186620 , J:190573 )

• 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)

disorganized mitochondrial cristae ( J:186620 )

• in the substantia nigra and amygdala

abnormal autophagy ( J:186620 , J:190573 )

• 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)

oxidative stress ( J:186620 , 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)

abnormal autophagy ( J:186620 , J:190573 )

• 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)

increased dopamine level ( J:186620 )

• 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

increased serotonin level ( J:186620 )

• 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

increased brain iron level ( J:186620 , J:190573 )

• 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)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease	DOID:10652		J:190573
Parkinson's disease	DOID:14330	OMIM:PS168600	J:190573
schizophrenia	DOID:5419	OMIM:181500	J:186620

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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