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Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican.

Howell MD, Gottschall PE - ASN Neuro (2012)

Bottom Line: Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity.In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs.In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

ABSTRACT
DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits.

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PNNs in LMC and Ts65Dn stratum oriensRepresentative images of WFA-positive PNNs in LMC (A) and Ts65Dn (B) SO (stratum oriens) and SP (stratum pyramidale). Individual PNNs were measured and the mean intensity and area determined (n = 141 LMC PNNs and n = 125 Ts65Dn PNNs). PNNs were then categorized based on their mean intensity per area (C). Note that category 1 indicates the lowest mean intensity/area. Mean intensity/area values for measured PNNs were also compared (D). PNNs were also categorized by area (E; category 1 is smallest area) and the values for area of PNNs was compared (F). (C) and (E) were analysed with Cochran–Armitage test for trend (see the text for details). *P<0.05 and **P<0.01 by Mann–Whitney U test. (A, B) Scale bar: 100 μm.
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Figure 7: PNNs in LMC and Ts65Dn stratum oriensRepresentative images of WFA-positive PNNs in LMC (A) and Ts65Dn (B) SO (stratum oriens) and SP (stratum pyramidale). Individual PNNs were measured and the mean intensity and area determined (n = 141 LMC PNNs and n = 125 Ts65Dn PNNs). PNNs were then categorized based on their mean intensity per area (C). Note that category 1 indicates the lowest mean intensity/area. Mean intensity/area values for measured PNNs were also compared (D). PNNs were also categorized by area (E; category 1 is smallest area) and the values for area of PNNs was compared (F). (C) and (E) were analysed with Cochran–Armitage test for trend (see the text for details). *P<0.05 and **P<0.01 by Mann–Whitney U test. (A, B) Scale bar: 100 μm.

Mentions: The increase in versican V2 in stratum oriens could be attributed to alterations in PNNs, of which versican V2 has been shown to be a component (Carulli et al., 2006; Deepa et al., 2006). PNNs were visualized with WFA, a lectin that binds to N-acetylgalactosamine residues (Figures 7A and 7B), and PNNs were categorized based on the mean intensity per area (category 1–4, with 1 being the lowest values). There were more Ts65Dn PNNs in category 1 and fewer in category 4 compared with LMCs (Figure 7C; χ2 = 3.922, df = 1, P = 0.0476) and an overall 21% decline in mean intensity/area (Figure 7D). This decrease could be due to an increase in PNN area so PNNs were also classified by area into categories as above. There was a greater number of Ts65Dn PNNs of the highest area (category 4) and lower number in the smallest area (category 1) compared with LMCs (Figure 7E; χ2 = 7.265, df = 1, P = 0.0070). Indeed, Ts65Dn PNNs exhibited a 24% increase in area compared with LMCs (Figure 7F). These data suggest that Ts65Dn stratum oriens PNNs encompass a larger neuronal surface than seen with LMC PNNs.


Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican.

Howell MD, Gottschall PE - ASN Neuro (2012)

PNNs in LMC and Ts65Dn stratum oriensRepresentative images of WFA-positive PNNs in LMC (A) and Ts65Dn (B) SO (stratum oriens) and SP (stratum pyramidale). Individual PNNs were measured and the mean intensity and area determined (n = 141 LMC PNNs and n = 125 Ts65Dn PNNs). PNNs were then categorized based on their mean intensity per area (C). Note that category 1 indicates the lowest mean intensity/area. Mean intensity/area values for measured PNNs were also compared (D). PNNs were also categorized by area (E; category 1 is smallest area) and the values for area of PNNs was compared (F). (C) and (E) were analysed with Cochran–Armitage test for trend (see the text for details). *P<0.05 and **P<0.01 by Mann–Whitney U test. (A, B) Scale bar: 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3275338&req=5

Figure 7: PNNs in LMC and Ts65Dn stratum oriensRepresentative images of WFA-positive PNNs in LMC (A) and Ts65Dn (B) SO (stratum oriens) and SP (stratum pyramidale). Individual PNNs were measured and the mean intensity and area determined (n = 141 LMC PNNs and n = 125 Ts65Dn PNNs). PNNs were then categorized based on their mean intensity per area (C). Note that category 1 indicates the lowest mean intensity/area. Mean intensity/area values for measured PNNs were also compared (D). PNNs were also categorized by area (E; category 1 is smallest area) and the values for area of PNNs was compared (F). (C) and (E) were analysed with Cochran–Armitage test for trend (see the text for details). *P<0.05 and **P<0.01 by Mann–Whitney U test. (A, B) Scale bar: 100 μm.
Mentions: The increase in versican V2 in stratum oriens could be attributed to alterations in PNNs, of which versican V2 has been shown to be a component (Carulli et al., 2006; Deepa et al., 2006). PNNs were visualized with WFA, a lectin that binds to N-acetylgalactosamine residues (Figures 7A and 7B), and PNNs were categorized based on the mean intensity per area (category 1–4, with 1 being the lowest values). There were more Ts65Dn PNNs in category 1 and fewer in category 4 compared with LMCs (Figure 7C; χ2 = 3.922, df = 1, P = 0.0476) and an overall 21% decline in mean intensity/area (Figure 7D). This decrease could be due to an increase in PNN area so PNNs were also classified by area into categories as above. There was a greater number of Ts65Dn PNNs of the highest area (category 4) and lower number in the smallest area (category 1) compared with LMCs (Figure 7E; χ2 = 7.265, df = 1, P = 0.0070). Indeed, Ts65Dn PNNs exhibited a 24% increase in area compared with LMCs (Figure 7F). These data suggest that Ts65Dn stratum oriens PNNs encompass a larger neuronal surface than seen with LMC PNNs.

Bottom Line: Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity.In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs.In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

ABSTRACT
DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits.

Show MeSH
Related in: MedlinePlus