Chondroitin-sulfate bearing proteoglycans termed lecticans are a major component of the extracellular matrix in the central nervous system and regulate neural plasticity. Proteolytic cleavage of lecticans by endogenous, extracellular metalloproteinases—matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs)—could loosen the extracellular matrix and promote neural plasticity. While evidence suggests MMPs contribute to neural plasticity, much less is known about the role ADAMTSs may play, and thus the purpose of this dissertation was to examine the influence of lecticans and their cleaving metalloproteinases on neural plasticity in vivo.
Two mouse models with either Adamts1 overexpression or knockout were examined to determine changes in lectican abundance and proteolytic processing and synapse abundance. Adamts1, located on human chromosome 21, is triplicated in the genetic disease Down syndrome (DS). In the first study, twenty months old Ts65Dn mice, a model of DS, exhibited abnormal deposition of the lectican versican V2 specifically in hippocampal stratum oriens that was associated with increased protein levels of postsynaptic density 95 kD (PSD-95) and positively correlated with impaired spatial learning. Perineuronal nets, a specialized form of the ECM that surrounds mainly inhibitory interneurons, were abnormally large in Ts65Dn stratum oriens, which may suggest abnormal inhibitory activity in the Ts65Dn hippocampus. In the second study, female ADAMTS1 knockout mice displayed marked reductions in frontal cortex synaptic protein levels that were not associated with altered abundance and proteolytic processing of lecticans, except for a marked accumulation of neurocan in female juvenile frontal cortex. These findings may suggest a nonproteolytic, direct action of ADAMTS1 on neural plasticity. The third study examined whether increased proteolytic processing of lecticans was associated with neural plasticity that accompanies environmental enrichment. Mice housed in enriched environments for one or four weeks exhibited no biological changes in lectican abundance and proteolytic processing, but mice enriched for four weeks displayed improved object discrimination. Variations amongst the same group of enriched and non-enriched mice, however, made it difficult to draw conclusions from this data. Nevertheless, several novel findings further support that lecticans and their cleaving metalloproteinases are associated with neural plasticity.
|Advisor:||Gottschall, Paul E.|
|Commitee:||Kelly, Thomas J., Prather, Paul L., Wenger, Galen R., Zheng, Fang|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/06(E), Dissertation Abstracts International|
|Keywords:||Adamts, Chondroitin sulfate proteoglycans, Cleaving metalloproteinases, Down syndrome, Environmental enrichment, Extracellular matrix, Mmp, Neural plasticity|
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