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Abstract
The chondroitin sulfate-bearing proteoglycans, also known as lecticans, are a major component of the extracellular matrix (ECM) in the central nervous system and regulate neural plasticity. Growing evidence indicates that endogenous, extracellular metalloproteinases that cleave lecticans mediate neural plasticity by altering the structure of ECM aggregates. The bulk of this in vivo data examined the matrix metalloproteinases, but another metalloproteinase family that cleaves lecticans, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), modulates structural plasticity in vitro, although few in vivo studies have tested this concept. Thus, the purpose of this study was to examine the neurological phenotype of a mouse deficient in ADAMTS1. Adamts1 mRNA was absent in the ADAMTS1 null mouse frontal cortex, but there was no change in the abundance or proteolytic processing of the prominent lecticans brevican and versican V2. However, there was a marked increase in the perinatal lectican neurocan in juvenile ADAMTS1 null female frontal cortex. More prominently, there were declines in synaptic protein levels in the ADAMTS1 null female, but not male, frontal cortex beginning at postnatal day 28. These synaptic marker declines did not affect learning or memory in the adult female ADAMTS1 null mice when tested with the radial-arm water maze. These results indicate that in vivo Adamts1 knockout leads to sexual dimorphism in frontal cortex synaptic protein levels. Since changes in lectican abundance and proteolytic processing did not accompany the synaptic protein declines, ADAMTS1 may play a nonproteolytic role in regulating neural plasticity.
Highlights
The extracellular matrix (ECM) in the central nervous system (CNS) surrounds perikarya and synapses, and functionally it is important in the regulation of neural plasticity [1]
Adamts5 and Adamts9 transcript abundance was significantly reduced in the male P8 ADAMTS1 null compared to wildtype frontal cortex with no difference at P28 or P130–160 (Figure 1C and 1D)
Adamts4 was more highly expressed at P28 and P130–160 compared to P8 for all mice (Figure 1B), Adamts5 and Adamts9 transcript abundances were generally highest at P8 (Figure 1C and 1D), and Adamts15 was expressed relatively consistently at all ages (Figure 1E)
Summary
The extracellular matrix (ECM) in the central nervous system (CNS) surrounds perikarya and synapses, and functionally it is important in the regulation of neural plasticity [1]. Perineuronal nets (PNNs) are a specialized form of the ECM that surrounds a minor subset of mainly inhibitory, parvalbumin-positive interneurons in the CNS [3]. Lecticans in PNNs and the neuropil are the key components of brain ECM that contribute to structural and functional plasticity, including the closure of critical periods early in development [4] and the stabilization of fear memories [5]. Lecticans are a major inhibitory component of the glial scar that develops after CNS injury, and they cause impaired axonal sprouting and regeneration and poor functional recovery [6]. While treatment with the bacterial enzyme chondroitinase ABC, which cleaves CS from lecticans, increased neurite outgrowth and improved functional recovery after CNS injury [7,8], lectican core proteins maintained at least partial neurite outgrowth inhibition in the absence of CS [9,10]
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