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14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders.

Xu X, Jaehne EJ, Greenberg Z, McCarthy P, Saleh E, Parish CL, Camera D, Heng J, Haas M, Baune BT, Ratnayake U, van den Buuse M, Lopez AF, Ramshaw HS, Schwarz Q - Sci Rep (2015)

Bottom Line: In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ(-/-) BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus.In contrast to our previous analyses, 14-3-3ζ(-/-) BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling.Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Frome Road, Adelaide, 5000, Australia.

ABSTRACT
Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ(-/-) mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ(-/-) phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ(-/-) BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus. In contrast to our previous analyses, 14-3-3ζ(-/-) BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.

No MeSH data available.


Related in: MedlinePlus

Abnormal connectivity of the hippocampus in 14-3-3ζ-deficient mice.Calbindin immunostaining of the infrapyramidal (IPMF) and the suprapyramidal (SPMF) mossy fibre trajectories. At P7 (i–iv) the calbindin mossy fibres are seen along the SPMF branch navigating away from the dentate gyrus (DG) in both 14-3-3ζ+/+ and 14-3-3ζ−/− mice. In 14-3-3ζ−/− mice the SPMF (green) branch aberrantly navigates among the NeuN positive (red) pyramidal cell somata (sp, arrowheads) in CA3. (iii’) higher magnification of boxed area in (i) and (iii”) higher magnification of calbindin staining from boxed area in (i). (iv’) Higher magnification of boxed area in (ii) and (iv”) higher magnification of calbindin staining from boxed area in (ii). At P56 (v-viii) the SPMF and IPMF branches of 14-3-3ζ−/− mice navigate aberrantly among the pyramidal cell somata (arrowheads) in CA3 and, the SPMF is shorter than in 14-3-3ζ+/+ mice (arrow). (vii and viii) higher magnification of the boxed regions in (v) and (vi), respectively. Scale bars = 100 μm.
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f3: Abnormal connectivity of the hippocampus in 14-3-3ζ-deficient mice.Calbindin immunostaining of the infrapyramidal (IPMF) and the suprapyramidal (SPMF) mossy fibre trajectories. At P7 (i–iv) the calbindin mossy fibres are seen along the SPMF branch navigating away from the dentate gyrus (DG) in both 14-3-3ζ+/+ and 14-3-3ζ−/− mice. In 14-3-3ζ−/− mice the SPMF (green) branch aberrantly navigates among the NeuN positive (red) pyramidal cell somata (sp, arrowheads) in CA3. (iii’) higher magnification of boxed area in (i) and (iii”) higher magnification of calbindin staining from boxed area in (i). (iv’) Higher magnification of boxed area in (ii) and (iv”) higher magnification of calbindin staining from boxed area in (ii). At P56 (v-viii) the SPMF and IPMF branches of 14-3-3ζ−/− mice navigate aberrantly among the pyramidal cell somata (arrowheads) in CA3 and, the SPMF is shorter than in 14-3-3ζ+/+ mice (arrow). (vii and viii) higher magnification of the boxed regions in (v) and (vi), respectively. Scale bars = 100 μm.

Mentions: Functional connectivity within the hippocampus is essential for high-order brain function25. Given the ectopic positions of neurons within the CA of 14-3-3ζ−/− mice we next asked if the mossy fibre connections between the dentate granular neurons and CA3 pyramidal neurons were also affected. Immunostaining with antibodies against calbindin showed that the suprapyramidal and infrapyramidal mossy fibre tracts were aberrantly aligned in the 14-3-3ζ−/− mice, compared to wildtype littermates (Fig. 3i–iv). Whereas the suprapyramidal tract formed tight axonal bundles along the apical surface of the CA3 pyramidal neurons in 14-3-3ζ+/+ mice, these mossy fibres navigated within the CA3 pyramidal layer of 14-3-3ζ−/− mice at P7 (Fig. 3iii,iv). In adult 14-3-3ζ+/+ brains, mossy fibres split into tightly bundled infrapyramidal and suprapyramidal branches lining the CA3 pyramidal layer. However, in 14-3-3ζ−/− mice the suprapyramidal fibres were diffuse and the infrapyramidal branch aberrantly navigated among the pyramidal cell layer and ectopically fused with the suprapyramidal branch (Fig. 3v–viii). Moreover, analysis of calbindin staining showed that the suprapyramidal branch failed to extend to the boundary of CA2/3 in 14-3-3ζ−/− adult brains (arrowheads, Fig. 3v,vi).


14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders.

Xu X, Jaehne EJ, Greenberg Z, McCarthy P, Saleh E, Parish CL, Camera D, Heng J, Haas M, Baune BT, Ratnayake U, van den Buuse M, Lopez AF, Ramshaw HS, Schwarz Q - Sci Rep (2015)

Abnormal connectivity of the hippocampus in 14-3-3ζ-deficient mice.Calbindin immunostaining of the infrapyramidal (IPMF) and the suprapyramidal (SPMF) mossy fibre trajectories. At P7 (i–iv) the calbindin mossy fibres are seen along the SPMF branch navigating away from the dentate gyrus (DG) in both 14-3-3ζ+/+ and 14-3-3ζ−/− mice. In 14-3-3ζ−/− mice the SPMF (green) branch aberrantly navigates among the NeuN positive (red) pyramidal cell somata (sp, arrowheads) in CA3. (iii’) higher magnification of boxed area in (i) and (iii”) higher magnification of calbindin staining from boxed area in (i). (iv’) Higher magnification of boxed area in (ii) and (iv”) higher magnification of calbindin staining from boxed area in (ii). At P56 (v-viii) the SPMF and IPMF branches of 14-3-3ζ−/− mice navigate aberrantly among the pyramidal cell somata (arrowheads) in CA3 and, the SPMF is shorter than in 14-3-3ζ+/+ mice (arrow). (vii and viii) higher magnification of the boxed regions in (v) and (vi), respectively. Scale bars = 100 μm.
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Related In: Results  -  Collection

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f3: Abnormal connectivity of the hippocampus in 14-3-3ζ-deficient mice.Calbindin immunostaining of the infrapyramidal (IPMF) and the suprapyramidal (SPMF) mossy fibre trajectories. At P7 (i–iv) the calbindin mossy fibres are seen along the SPMF branch navigating away from the dentate gyrus (DG) in both 14-3-3ζ+/+ and 14-3-3ζ−/− mice. In 14-3-3ζ−/− mice the SPMF (green) branch aberrantly navigates among the NeuN positive (red) pyramidal cell somata (sp, arrowheads) in CA3. (iii’) higher magnification of boxed area in (i) and (iii”) higher magnification of calbindin staining from boxed area in (i). (iv’) Higher magnification of boxed area in (ii) and (iv”) higher magnification of calbindin staining from boxed area in (ii). At P56 (v-viii) the SPMF and IPMF branches of 14-3-3ζ−/− mice navigate aberrantly among the pyramidal cell somata (arrowheads) in CA3 and, the SPMF is shorter than in 14-3-3ζ+/+ mice (arrow). (vii and viii) higher magnification of the boxed regions in (v) and (vi), respectively. Scale bars = 100 μm.
Mentions: Functional connectivity within the hippocampus is essential for high-order brain function25. Given the ectopic positions of neurons within the CA of 14-3-3ζ−/− mice we next asked if the mossy fibre connections between the dentate granular neurons and CA3 pyramidal neurons were also affected. Immunostaining with antibodies against calbindin showed that the suprapyramidal and infrapyramidal mossy fibre tracts were aberrantly aligned in the 14-3-3ζ−/− mice, compared to wildtype littermates (Fig. 3i–iv). Whereas the suprapyramidal tract formed tight axonal bundles along the apical surface of the CA3 pyramidal neurons in 14-3-3ζ+/+ mice, these mossy fibres navigated within the CA3 pyramidal layer of 14-3-3ζ−/− mice at P7 (Fig. 3iii,iv). In adult 14-3-3ζ+/+ brains, mossy fibres split into tightly bundled infrapyramidal and suprapyramidal branches lining the CA3 pyramidal layer. However, in 14-3-3ζ−/− mice the suprapyramidal fibres were diffuse and the infrapyramidal branch aberrantly navigated among the pyramidal cell layer and ectopically fused with the suprapyramidal branch (Fig. 3v–viii). Moreover, analysis of calbindin staining showed that the suprapyramidal branch failed to extend to the boundary of CA2/3 in 14-3-3ζ−/− adult brains (arrowheads, Fig. 3v,vi).

Bottom Line: In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ(-/-) BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus.In contrast to our previous analyses, 14-3-3ζ(-/-) BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling.Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Frome Road, Adelaide, 5000, Australia.

ABSTRACT
Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ(-/-) mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ(-/-) phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ(-/-) BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus. In contrast to our previous analyses, 14-3-3ζ(-/-) BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.

No MeSH data available.


Related in: MedlinePlus