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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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Altered functionality of the DG in O377 mutants. a Experimental arrangement used for the VSDI experiments depicted and quantified in b–d. The artificial cut was made to prevent CA1 neuronal activity resulting from action potentials in fibers of the temporoammonic pathway. b VSDI filmstrip of the spread of neuronal activity evoked by a single electrical stimulation pulse (200 μs, 15 V) delivered via an extracellular electrode to the perforant path. Warmer colors represent stronger neuronal activity. c VSDI recording traces from two of the in d quantified experiments. As the VSDI measure of neuronal activity, we used ROI-extracted, fast, depolarization-mediated imaging signals (FDSs; see also the “Materials and methods” section). d Increased translation of input (ROI1-FDS)-to-output (ROI2-FDS) neuronal activity in the DG of O377 mutants (for each condition, n = 8 slices from 4 mice). Results are presented as mean ± SEM. **p < 0.01 (unpaired t test)
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Fig6: Altered functionality of the DG in O377 mutants. a Experimental arrangement used for the VSDI experiments depicted and quantified in b–d. The artificial cut was made to prevent CA1 neuronal activity resulting from action potentials in fibers of the temporoammonic pathway. b VSDI filmstrip of the spread of neuronal activity evoked by a single electrical stimulation pulse (200 μs, 15 V) delivered via an extracellular electrode to the perforant path. Warmer colors represent stronger neuronal activity. c VSDI recording traces from two of the in d quantified experiments. As the VSDI measure of neuronal activity, we used ROI-extracted, fast, depolarization-mediated imaging signals (FDSs; see also the “Materials and methods” section). d Increased translation of input (ROI1-FDS)-to-output (ROI2-FDS) neuronal activity in the DG of O377 mutants (for each condition, n = 8 slices from 4 mice). Results are presented as mean ± SEM. **p < 0.01 (unpaired t test)

Mentions: Preparation and staining of brain slices, VSDI, and data analysis were performed as previously described (von Wolff et al. 2011) with the following modifications. We used a custom-made monopolar tungsten electrode (Teflon-insulated to the tip of 50 μm in diameter) for electrical stimulation of the perforant path. This electrode allowed for very precise placement into the neuronal tissue and did not interfere with VSDI (e.g., by producing irritating shadows as is seen with other electrodes). A highly localized electrical stimulation was achieved by positioning the indifferent electrode far away from the slice in the recording chamber. The electrode was placed on the visually identified perforant path near its entry zone to the DG (Fig. 6a). ROI1 and ROI2 were created by the polygon-drawing function of the MiCAM02 software.


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)

Altered functionality of the DG in O377 mutants. a Experimental arrangement used for the VSDI experiments depicted and quantified in b–d. The artificial cut was made to prevent CA1 neuronal activity resulting from action potentials in fibers of the temporoammonic pathway. b VSDI filmstrip of the spread of neuronal activity evoked by a single electrical stimulation pulse (200 μs, 15 V) delivered via an extracellular electrode to the perforant path. Warmer colors represent stronger neuronal activity. c VSDI recording traces from two of the in d quantified experiments. As the VSDI measure of neuronal activity, we used ROI-extracted, fast, depolarization-mediated imaging signals (FDSs; see also the “Materials and methods” section). d Increased translation of input (ROI1-FDS)-to-output (ROI2-FDS) neuronal activity in the DG of O377 mutants (for each condition, n = 8 slices from 4 mice). Results are presented as mean ± SEM. **p < 0.01 (unpaired t test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3824278&req=5

Fig6: Altered functionality of the DG in O377 mutants. a Experimental arrangement used for the VSDI experiments depicted and quantified in b–d. The artificial cut was made to prevent CA1 neuronal activity resulting from action potentials in fibers of the temporoammonic pathway. b VSDI filmstrip of the spread of neuronal activity evoked by a single electrical stimulation pulse (200 μs, 15 V) delivered via an extracellular electrode to the perforant path. Warmer colors represent stronger neuronal activity. c VSDI recording traces from two of the in d quantified experiments. As the VSDI measure of neuronal activity, we used ROI-extracted, fast, depolarization-mediated imaging signals (FDSs; see also the “Materials and methods” section). d Increased translation of input (ROI1-FDS)-to-output (ROI2-FDS) neuronal activity in the DG of O377 mutants (for each condition, n = 8 slices from 4 mice). Results are presented as mean ± SEM. **p < 0.01 (unpaired t test)
Mentions: Preparation and staining of brain slices, VSDI, and data analysis were performed as previously described (von Wolff et al. 2011) with the following modifications. We used a custom-made monopolar tungsten electrode (Teflon-insulated to the tip of 50 μm in diameter) for electrical stimulation of the perforant path. This electrode allowed for very precise placement into the neuronal tissue and did not interfere with VSDI (e.g., by producing irritating shadows as is seen with other electrodes). A highly localized electrical stimulation was achieved by positioning the indifferent electrode far away from the slice in the recording chamber. The electrode was placed on the visually identified perforant path near its entry zone to the DG (Fig. 6a). ROI1 and ROI2 were created by the polygon-drawing function of the MiCAM02 software.

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
Related in: MedlinePlus