Phenotypes associated with this allele

• Allele Symbol: Tg(Gfap-cre)73.12Mvs
• Allele Name: transgene insertion 73.12, Michael V Sofroniew
• Allele ID: MGI:3522215
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Rai1^tm2.1Luo/Rai1^tm2.1Luo Tg(Gfap-cre)73.12Mvs/?	either: (involves: 129S1/Sv * BALB/c * C57BL/6 * C57BL/6NHsd) or (involves: 129S1/Sv * 129X1/SvJ * BALB/c * C57BL/6 * C57BL/6NHsd)	MGI:5817666
cn2	Gpc5^tm1c(KOMP)Wtsi/Gpc5^tm1c(KOMP)Wtsi Tg(Gfap-cre)73.12Mvs/0	involves: 129S4/SvJaeSor * BALB/c * C57BL/6J * C57BL/6N	MGI:8221971
cn3	Smo^tm2Amc/Smo^tm2Amc Tg(Gfap-cre)73.12Mvs/0	involves: 129X1/SvJ * BALB/c * C57BL/6NHsd	MGI:4838615
cn4	Tg(Gfap-cre)73.12Mvs/0 Twnk^tm1.1Suom/Twnk^tm1.1Suom	involves: BALB/c * C57BL/6NHsd * C57BL/6JOlaHsd	MGI:8235453

Genotype
MGI:5817666

cn1

• Allelic Composition: Rai1^tm2.1Luo/Rai1^tm2.1Luo; Tg(Gfap-cre)73.12Mvs/?
• Genetic Background: either: (involves: 129S1/Sv * BALB/c * C57BL/6 * C57BL/6NHsd) or (involves: 129S1/Sv * 129X1/SvJ * BALB/c * C57BL/6 * C57BL/6NHsd)

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

normal phenotype

no abnormal phenotype detected ( J:237687 )

• mice do not exhibit differences in behavior, motor function or body weight

Genotype
MGI:8221971

cn2

• Allelic Composition: Gpc5^{tm1c(KOMP)Wtsi}/Gpc5^{tm1c(KOMP)Wtsi}; Tg(Gfap-cre)73.12Mvs/0
• Genetic Background: involves: 129S4/SvJaeSor * BALB/c * C57BL/6J * C57BL/6N
• Cell Lines: EPD0574_1_B09

nervous system

abnormal synaptic vesicle number ( J:363787 )

• at P28, thalamocortical synapses show a significant decrease in the number of synaptic vesicles within multisynaptic boutons, with no change at monosynaptic connections

abnormal CNS synapse formation ( J:363787 )

• mice show abnormal glutamatergic synapse maturation and stabilization in the developing visual cortex (VC) during the critical period of synapse maturation

• at P28 (peak of the critical period), thalamocortical synapses within the primary VC show structural immaturity whereas intracortical synapses show functional immaturity with reduced incorporation of GLUA2 subunits into AMPA-type glutamate receptors (AMPARs)

delayed CNS synapse formation ( J:363787 )

• by P120, intracortical synapses exhibit normalized VGLUT1and GLUA2 puncta numbers and colocalization of VGLUT1 and GLUA2 in L1 and L2/3, while thalamocortical synapses show restored VGLUT2 puncta volume in L1 and L4, indicating recovery from the synaptic alterations detected at P28

abnormal synaptic bouton morphology ( J:363787 )

• at P28, thalamocortical synapses show a ~40% decrease in the volume of VGLUT2 puncta in layers L1 and L4 of the VC, indicating smaller presynaptic terminals

• analysis of thalamocortical axons in L4 shows that the average terminal volume of presynaptic boutons is significantly reduced, driven by a significant decrease in the volume of multisynaptic boutons, with no change in the volume of monosynaptic connections

• moreover, both the average number of postsynaptic partners at a multisynaptic bouton and the maximum number of synapses observed at a single bouton are increased

abnormal dendritic spine morphology ( J:363787 )

• at P28, L4 thalamocortical synapses show a shift in dendritic spine morphology toward a more immature state at monosynaptic, but not at multisynaptic, connections

• in contrast, L2/3 pyramidal neurons consisting of predominantly intracortical synapses show no gross abnormalities in dendritic spine structure at P28

abnormal dendritic mushroom spine morphology ( J:363787 )

• at P28, L4 thalamocortical synapses show a significant decrease in the % of mushroom dendritic spines at monosynaptic connections

abnormal dendritic thin spine morphology ( J:363787 )

• at P28, L4 thalamocortical synapses show a significant increase in the % of thin dendritic spines at monosynaptic connections

abnormal postsynaptic density morphology ( J:363787 )

• at P28, thalamocortical synapses in L4 show a decreased postsynaptic density (PSD) surface area and more postsynaptic partners at multisynaptic connections

• decrease in PSD surface area is seen at dendritic spines opposed to both monosynaptic and multisynaptic boutons

abnormal excitatory synapse morphology ( J:363787 )

• at P28, intracortical excitatory synapses within the VC show a deceased protein level of GLUA2 (a postsynaptic marker for mature synapses) specifically in layers L2/3: colocalization of GLUA2 and VGLUT1 (a presynaptic marker for intracortical synapses) in L2/3 is reduced by ~30%, driven by a decrease in GLUA2 puncta in L2/3 but not in L1; however, no change is noted in the number of presynaptic VGLUT1 terminals, number of postsynaptic GLUA1 puncta (immature synapses) in L1 or L2/3, or in the colocalization of GLUA1 and VGLUT1 in either layer

• at P28, thalamocortical excitatory synapses within the VC exhibit a ~40% decrease in the volume of VGLUT2 puncta (a presynaptic marker for thalamocortical synapses) in both L1 and L4; however, no change is noted the number of presynaptic VGLUT2 terminals, colocalization of VGLUT2 with postsynaptic GLUA1 or GLUA2 in L1 or L4, or in the number of GLUA1, GLUA2 or VGLUT2 puncta in either layer

• analysis of thalamocortical axons in L4 indicates that thalamocortical synapses are structurally immature, with smaller presynaptic boutons, decreased postsynaptic density area, and more postsynaptic partners at multisynaptic connections

• AAV2/5 mediated HA-GPC5 overexpression in VC astrocytes is sufficient to increase the total level of GLUA2 in L2/3 intracortical synapses, without impacting VGLUT1 puncta number or colocalization of VGLUT1-GLUA2 in L2/3

• however, overexpression of GPC5 in L4 thalamocortical synapses has no impact on VGLUT2 terminal volume

abnormal synaptic plasticity ( J:363787 )

• mice show enhanced ocular dominance plasticity in response to visual deprivation in adulthood: when monocularly enucleated (ME) at P120, mice show a significant increase in the width of the Arc zone at 5 days after ME relative to 12 h after ME (baseline innervation); moreover, the width of the Arc zone after 5 days of ME is significantly larger than that in wild-type controls

• however, no change in large-scale ocular dominance plasticity is detected when ME is performed at P28 (during the critical period)

decreased excitatory postsynaptic current amplitude ( J:363787 )

• at P28, whole-cell patch clamp recordings from L2/3 pyramidal neurons in acute slices of the primary visual cortex show that AMPA-mediated spontaneous excitatory postsynaptic currents (sEPSCs) are significantly reduced in amplitude

• however, no major change is noted in the sEPSC interevent interval, 10%-90% rise time or decay time

cellular

abnormal synaptic vesicle number ( J:363787 )

• at P28, thalamocortical synapses show a significant decrease in the number of synaptic vesicles within multisynaptic boutons, with no change at monosynaptic connections

Genotype
MGI:4838615

cn3

• Allelic Composition: Smo^tm2Amc/Smo^tm2Amc; Tg(Gfap-cre)73.12Mvs/0
• Genetic Background: involves: 129X1/SvJ * BALB/c * C57BL/6NHsd

nervous system

nervous system phenotype ( J:165495 )

N • mice exhibit normal forebrain morphology and cytoarchitecture

N • the number of astrocytes in the cortex is normal

astrocytosis ( J:165495 )

• mild in the cortex

cellular

astrocytosis ( J:165495 )

• mild in the cortex

Genotype
MGI:8235453

cn4

• Allelic Composition: Tg(Gfap-cre)73.12Mvs/0; Twnk^tm1.1Suom/Twnk^tm1.1Suom
• Genetic Background: involves: BALB/c * C57BL/6NHsd * C57BL/6JOlaHsd

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:304258 )

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age

• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation

premature death ( J:304258 )

• mice reach humane end point by 5-6 months of age

• mice fed a ketogenic diet after weaning before disease manifestation reach humane end point after 9.5 weeks of treatment

growth/size/body

weight loss ( J:304258 )

• mice show progressive weight loss starting from 2-3 months of age

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment

homeostasis/metabolism

abnormal homeostasis ( J:304258 )

• saccharopine, the degradation produce of lysine, is the most significantly increased metabolite

• rapamycin treatment partially rescues the saccaropine increase

• the level of sacccharopine is further increased in ketogenic diet-fed mice

decreased aspartic acid level ( J:304258 )

• aspartate levels are reduced in the brain

• aspartate, produced in the mitochondria, is decreased in ketogenic diet-fed mice

increased glycine level ( J:304258 )

• 3.6-fold increase of glycine in the brain

• the elevated glycine level is normalized by rapamycin treatment

• level of glycine is further increased in ketogenic diet-fed mice

increased proline level ( J:304258 )

• increase in proline levels in the brain

increased serine level ( J:304258 )

• 4.5- and 3.6-fold increase of serine and glycine in the brain, indicating induction of de novo serine biosynthesis

• the elevated serine level is normalized by rapamycin treatment

• level of serine is further increased in ketogenic diet-fed mice, despite de novo serine synthesis enzyme expression levels not being detected

abnormal enzyme/coenzyme level ( J:304258 )

• mice show increased expression of transsulfuration enzymes

• expression of transsulfuration enzymes is increased in ketogenic diet-fed mice

abnormal lipid metabolism ( J:304258 )

• several lipid metabolites are slightly decreased in the brain

• rapamycin has no effect on lipid metabolites in the brain

abnormal nucleotide metabolism ( J:304258 )

• several purine precursors or degradation products are increased in the brain

• uracil, a pyrimidine metabolite, is increased in the brain

• ATP, ADP, UDP, and FAD decline in ketogenic diet-fed mutant mice but not in controls, indicating an imbalance of nucleotide metabolism and high-energy phosphate donors

increased susceptibility to xenobiotic induced morbidity/mortality ( J:304258 )

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age

• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation

increased physiological sensitivity to xenobiotic ( J:304258 )

• treatment with rapamycin exacerbates spongiosis, gliosis and mitochondrial integrated stress response in the brain

• rapamycin treatment increases methionine levels and glutamine levels, suggesting either increased production or decreased usage

nervous system

gliosis ( J:304258 )

• progression of reactive gliosis is unaffected by rapamycin

• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet

spongiform encephalopathy ( J:304258 )

• 2.3-month-old mice show sparsely located holes in the brain parenchyma

• rapamycin treatment started at 1.5 months or 3 months of age does not improve but increases progression of mitochondrial spongiotic encephalopathy

• mice fed a ketogenic diet after weaning before disease manifestation, show worsening of brain pathology, with more severe spongiosis and gliosis than in mice fed a chow diet

cellular

gliosis ( J:304258 )

• progression of reactive gliosis is unaffected by rapamycin

• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet

abnormal mitochondrial physiology ( J:304258 )

• mitochondrial integrated stress response, as indicated by activation of related genes, is induced in the brain of 5.5-month-old mice but not in 2.3-month-old mice

• mice fed a ketogenic diet show further induction of the mitochondrial integrated stress response

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
mitochondrial DNA depletion syndrome		DOID:0070329	OMIM:PS603041	J:304258