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Crybb2 coding for βB2-crystallin affects sensorimotor gating and hippocampal function.

Sun M, Hölter SM, Stepan J, Garrett L, Genius J, Kremmer E, Hrabě de Angelis M, Wurst W, Lie DC, Bally-Cuif L, Eder M, Rujescu D, Graw J - Mamm. Genome (2013)

Bottom Line: These results point to an important function of βB2-crystallin in the hippocampal network.They indicate pleiotropic effects of mutations in the Crybb2 gene, which previously had been considered to be specific to the ocular lens.Moreover, our results are the first to demonstrate that βB2-crystallin has a role in hippocampal function and behavioral phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Developmental Genetics, Helmholtz Center Munich - National Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.

ABSTRACT
βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens. This gene, however, is also expressed in several regions of the mammalian brain, although its function in this organ remains entirely unknown. To unravel some aspects of its function in the brain, we combined behavioral, neuroanatomical, and physiological analyses in a novel Crybb2 mouse mutant, O377. Behavioral tests with male O377 mutants revealed altered sensorimotor gating, suggesting modified neuronal functions. Since these mouse mutants also displayed reduced hippocampal size, we concentrated further investigations on the hippocampus. Free intracellular Ca(2+) levels were increased and apoptosis was enhanced in the hippocampus of O377 mutants. Moreover, the expression of the gene encoding calpain 3 (gene symbol Capn3) was elevated and the expression of genes coding for the NMDA receptor subunits was downregulated. Additionally, the number of parvalbumin-positive interneurons was decreased in the hippocampus but not in the cortex of the mutants. High-speed voltage-sensitive dye imaging demonstrated an increased translation of input-to-output neuronal activity in the dentate gyrus of this Crybb2 mutant. These results point to an important function of βB2-crystallin in the hippocampal network. They indicate pleiotropic effects of mutations in the Crybb2 gene, which previously had been considered to be specific to the ocular lens. Moreover, our results are the first to demonstrate that βB2-crystallin has a role in hippocampal function and behavioral phenotypes. This model can now be further explored by future experiments.

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Apoptotic cell death is increased in young O377 mutants. a–h Confocal images of anti-caspase-3 staining (red) in 2-week-old wild-type (WT, left panel) and O377 mice (right panel) in the ventral CA (upper panel, a–d) and in the DG (lower panel, e–h). DAPI staining is given in blue. The boxed area is given below in a higher magnification. In i, j, the values are normalized to wild-type mice at the age of 3 months and given in % (T = 100 %). i Density of caspase-3-positive cells in WT and O377 mutants in the ventral DG (WT = 100 %). j Density of caspase-3-positive cells in wild-type and O377 mutants in the ventral CA (WT = 100 %). *p ≤ 0.05, Student’s t test, n ≥ 4. Scale bar 40 μm; error bar SEM
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Fig2: Apoptotic cell death is increased in young O377 mutants. a–h Confocal images of anti-caspase-3 staining (red) in 2-week-old wild-type (WT, left panel) and O377 mice (right panel) in the ventral CA (upper panel, a–d) and in the DG (lower panel, e–h). DAPI staining is given in blue. The boxed area is given below in a higher magnification. In i, j, the values are normalized to wild-type mice at the age of 3 months and given in % (T = 100 %). i Density of caspase-3-positive cells in WT and O377 mutants in the ventral DG (WT = 100 %). j Density of caspase-3-positive cells in wild-type and O377 mutants in the ventral CA (WT = 100 %). *p ≤ 0.05, Student’s t test, n ≥ 4. Scale bar 40 μm; error bar SEM

Mentions: Next, we investigated apoptosis using immunohistochemistry with an antibody against cleaved caspase-3 (Fig. 2). In 2-week-old mice, the density of apoptotic cells was found to be increased by 75.2 % in the ventral DG of O377 mutants in comparison to the wild-type mice; in the ventral CA of the O377 mutants, it was twice that of the wild-type animals. Interestingly, this difference was smaller at 1 month and disappeared at 3 months of age. Immunofluorescence for double labeling of parvalbumin and cleaved caspase-3 was also performed; however, no double-labeled cells were detected. Together, this suggested that the reduced size of the hippocampus (and concomitantly, also the number of parvalbumin-positive neurons) of βB2-crystallin mutants might be an indirect effect of a wave of cell death prominent between 2 and 4 weeks after birth.Fig. 2


Crybb2 coding for βB2-crystallin affects sensorimotor gating and hippocampal function.

Sun M, Hölter SM, Stepan J, Garrett L, Genius J, Kremmer E, Hrabě de Angelis M, Wurst W, Lie DC, Bally-Cuif L, Eder M, Rujescu D, Graw J - Mamm. Genome (2013)

Apoptotic cell death is increased in young O377 mutants. a–h Confocal images of anti-caspase-3 staining (red) in 2-week-old wild-type (WT, left panel) and O377 mice (right panel) in the ventral CA (upper panel, a–d) and in the DG (lower panel, e–h). DAPI staining is given in blue. The boxed area is given below in a higher magnification. In i, j, the values are normalized to wild-type mice at the age of 3 months and given in % (T = 100 %). i Density of caspase-3-positive cells in WT and O377 mutants in the ventral DG (WT = 100 %). j Density of caspase-3-positive cells in wild-type and O377 mutants in the ventral CA (WT = 100 %). *p ≤ 0.05, Student’s t test, n ≥ 4. Scale bar 40 μm; error bar SEM
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3824278&req=5

Fig2: Apoptotic cell death is increased in young O377 mutants. a–h Confocal images of anti-caspase-3 staining (red) in 2-week-old wild-type (WT, left panel) and O377 mice (right panel) in the ventral CA (upper panel, a–d) and in the DG (lower panel, e–h). DAPI staining is given in blue. The boxed area is given below in a higher magnification. In i, j, the values are normalized to wild-type mice at the age of 3 months and given in % (T = 100 %). i Density of caspase-3-positive cells in WT and O377 mutants in the ventral DG (WT = 100 %). j Density of caspase-3-positive cells in wild-type and O377 mutants in the ventral CA (WT = 100 %). *p ≤ 0.05, Student’s t test, n ≥ 4. Scale bar 40 μm; error bar SEM
Mentions: Next, we investigated apoptosis using immunohistochemistry with an antibody against cleaved caspase-3 (Fig. 2). In 2-week-old mice, the density of apoptotic cells was found to be increased by 75.2 % in the ventral DG of O377 mutants in comparison to the wild-type mice; in the ventral CA of the O377 mutants, it was twice that of the wild-type animals. Interestingly, this difference was smaller at 1 month and disappeared at 3 months of age. Immunofluorescence for double labeling of parvalbumin and cleaved caspase-3 was also performed; however, no double-labeled cells were detected. Together, this suggested that the reduced size of the hippocampus (and concomitantly, also the number of parvalbumin-positive neurons) of βB2-crystallin mutants might be an indirect effect of a wave of cell death prominent between 2 and 4 weeks after birth.Fig. 2

Bottom Line: These results point to an important function of βB2-crystallin in the hippocampal network.They indicate pleiotropic effects of mutations in the Crybb2 gene, which previously had been considered to be specific to the ocular lens.Moreover, our results are the first to demonstrate that βB2-crystallin has a role in hippocampal function and behavioral phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Developmental Genetics, Helmholtz Center Munich - National Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.

ABSTRACT
βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens. This gene, however, is also expressed in several regions of the mammalian brain, although its function in this organ remains entirely unknown. To unravel some aspects of its function in the brain, we combined behavioral, neuroanatomical, and physiological analyses in a novel Crybb2 mouse mutant, O377. Behavioral tests with male O377 mutants revealed altered sensorimotor gating, suggesting modified neuronal functions. Since these mouse mutants also displayed reduced hippocampal size, we concentrated further investigations on the hippocampus. Free intracellular Ca(2+) levels were increased and apoptosis was enhanced in the hippocampus of O377 mutants. Moreover, the expression of the gene encoding calpain 3 (gene symbol Capn3) was elevated and the expression of genes coding for the NMDA receptor subunits was downregulated. Additionally, the number of parvalbumin-positive interneurons was decreased in the hippocampus but not in the cortex of the mutants. High-speed voltage-sensitive dye imaging demonstrated an increased translation of input-to-output neuronal activity in the dentate gyrus of this Crybb2 mutant. These results point to an important function of βB2-crystallin in the hippocampal network. They indicate pleiotropic effects of mutations in the Crybb2 gene, which previously had been considered to be specific to the ocular lens. Moreover, our results are the first to demonstrate that βB2-crystallin has a role in hippocampal function and behavioral phenotypes. This model can now be further explored by future experiments.

Show MeSH