Evidence for proteolytic cleavage of brevican by the ADAMTSs in the dentate gyrus after excitotoxic lesion of the mouse entorhinal cortex
© Mayer et al; licensee BioMed Central Ltd. 2005
Received: 09 May 2005
Accepted: 25 August 2005
Published: 25 August 2005
Brevican is a member of the lectican family of aggregating extracellular matrix (ECM) proteoglycans that bear chondroitin sulfate (CS) chains. It is highly expressed in the central nervous system (CNS) and is thought to stabilize synapses and inhibit neural plasticity and as such, neuritic or synaptic remodeling would be less likely to occur in regions with intact and abundant, lectican-containing, ECM complexes. Neural plasticity may occur more readily when these ECM complexes are broken down by endogenous proteases, the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs), that selectively cleave the lecticans. The purpose of these experiments was to determine whether the production of brevican or the ADAMTS-cleaved fragments of brevican were altered after deafferentation and reinnervation of the dentate gyrus via entorhinal cortex lesion (ECL).
In the C57Bl6J mouse, synaptic density in the molecular layer of the dentate gyrus, as measured by synaptophysin levels in ELISA, was significantly attenuated 2 days (nearly 50% of contralateral) and 7 days after lesion and returned to levels not different from the contralateral region at 30 days. Immunoreactive brevican in immunoblot was elevated 2 days after lesion, whereas there was a significant increase in the proteolytic product at 7, but not 30 days post-lesion. ADAMTS activity, estimated using the ratio of the specific ADAMTS-derived brevican fragment and intact brevican levels was increased at 7 days, but was not different from the contralateral side at 2 or 30 days after deafferentation.
These findings indicate that ADAMTS activity in the dentate outer molecular layer (OML) is elevated during the initial synaptic reinnervation period (7 days after lesion). Therefore, proteolytic processing of brevican appears to be a significant extracellular event in the remodeling of the dentate after EC lesion, and may modulate the process of sprouting and/or synaptogenesis.
Neurons of the entorhinal cortex (EC) send unidirectional, afferent projections to the hippocampus, where terminals synapse on granule cell dendrites in the outer molecular layer (OML) of the dentate gyrus . Interruption of entorhinal input to the dentate gyrus, by chemical lesion or severing the afferent fibers, causes anterograde degeneration of the axon terminals and stimulates sprouting of viable fibers from this and other neuronal circuits [2–5]. The entorhinal cortex lesion (ECL) has been used as a model of neural plasticity for more than three decades . To identify and innervate a target after injury or during development, growing neuron terminals must traverse through a complex extracellular milieu that consists of soluble factors, cell surface adhesive ligands and an extracellular matrix (ECM) along the way toward its target. The growing terminal samples this milieu, and appropriate protein-protein binding and activation regulates the direction and extent of growth, terminal sprouting, and likely synaptogenesis. For example, certain ECM molecules such as laminin are permissive toward neurite outgrowth, whereas others, such as the highly negatively charged, proteoglycans (PGs) substituted with chondroitin sulfate (CS) (ie. versican, neurocan, aggrecan and brevican, in general, lecticans), inhibit neurite outgrowth on permissive substrates [7–9]. Interestingly, the expression of several lecticans, including brevican is markedly up-regulated during the neural plasticity response that occurs following ECL .
The lectican PGs are the most abundant ECM molecules in the adult, uninjured central nervous system (CNS) and of these brevican is the most highly expressed [11, 12]. Brevican and other lecticans are found in perineuronal nets and throughout the neuropil and are components of ECM aggregate complexes that are thought to stabilize synapses in neural networks and inhibit neurite outgrowth [13, 14]. Most evidence suggests that the CS component in these complexes provides the inhibitory signal toward neurite outgrowth, although the protein core plays a role as well [8, 15]. However, proteolytic cleavage of the brevican core protein may "loosen" the aggregated complexes and change the extracellular environment to one that is more permissive for neural plasticity to occur [14, 16, 17]. A significant proportion of brevican in the adult CNS exists as a fragment formed by proteolytic cleavage of the protein core, suggesting that this mechanism may play a role in experience-dependent and other forms of neural plasticity in the uninjured, adult. In addition, in disorders such as Alzheimer's disease, alterations in the ECM may be related to diminished synaptic plasticity and therefore play a role in cognitive dysfunction.
Others have demonstrated changes in the levels and activity of matrix metalloproteinases (MMPs) in the deafferented neuropil after various lesions, however in these experiments, the substrate proteolytically processed by the MMPs was not identified [20, 21]. Nonetheless, changes in structure and function that were associated with lesion-induced sprouting were reversed by MMP inhibitors . Lesions produced by systemic injection of kainic acid produce wide-spread neuronal degeneration in the CNS, including the EC and stimulate expression of the MMPs and the ADAMTSs [16, 23]. In response to this lesion, the abundance of the neoepitope fragment generated by ADAMTS-cleavage of brevican was markedly elevated in the OML of the dentate gyrus. This increase was preceded by elevated ADAMTS1 and ADAMTS4 mRNA expression in dentate granule neurons . Although these results suggest that proteolytic processing of brevican appears to be a significant extracellular event in the remodeling of the dentate after ECL, because of the widespread neuronal death, it was difficult to associate these two particular endpoints as individual, yet associated events involved in neural plasticity. Thus, we decided to employ the classical ECL model in the C57Bl6 mouse, thereby discretely disrupting synaptic innervation of the molecular layer of the dentate gyrus. Our intention was to observe any altered expression of brevican and the ADAMTSs that may be associated with reinnervation of the injured area 2, 7 and 30 days after lesion.
Expression of ADAMTS-derived, brevican fragment
Deafferentation and neural plasticity in the dentate gyrus
Two days after lesion, synaptophysin levels as detected by ELISA, declined by 46% in the ipsilateral dentate compared to the contralateral side (p = 0.039) (Fig. 5E). This trend was sustained at seven days post-lesion, and synaptophysin levels were 41% of the contralateral value (p = 0.033) (Fig. 5E). However, when tissue was examined thirty days post-lesion, synaptophysin concentrations were not different from the control side. This observation shows there is a complete reinnervation of the OML after ECL (Fig. 5E).
The decline in the level of synaptophysin concentrations in the tissue from the "dentate punch" on the ipsilateral side compared to the contralateral side indicates that there was denervation of cortical input to the dentate molecular layer. The question of interest was, however, were there associated changes in the abundance and proteolysis of brevican in this region of neural plasticity?
Abundance and proteolysis of brevican after ECL
The purpose of this study was to determine whether the catabolism of brevican is involved in mechanisms of neural plasticity in the hippocampus, and to accomplish this, synaptic input to the OML of the dentate gyrus was denervated by excitotoxic lesion in the lateral EC. Two days after lesion, synaptic input into the OML was significantly reduced and this was accompanied by an increase in the production of full length, intact brevican. At seven days, while brevican levels returned to baseline, a significant increase in the ADAMTS-derived, C-terminally truncated, brevican fragment was observed during this initial, sprouting and reinnervation period. This implies that there was an increase in ADAMTS activity in the OML during the highly plastic, regenerative phase. However at thirty days post-lesion, there was complete reinnervation of the OML on the ipsilateral side, as synaptic density, brevican and ADAMTS activity were not different from the contralateral side at this time point. These results indicate that the ADAMTSs and their substrate, brevican, that is abundant in the CNS, have a regulatory function in neural plasticity and support earlier data that had demonstrated important actions for the ADAMTSs in plasticity after seizure-induced hippocampal lesion .
Previous studies have examined the role of matrix-altering proteases in synaptic plasticity after CNS lesion. The expression of the matrix metalloproteinases (MMPs), MMP-9 and MMP-2, have been shown to be increased in various regions of the hippocampus after seizure-induced lesion [21, 23, 27, 28]. MMP-3 concentrations were elevated in the molecular layer of the dentate after traumatic brain injury . More specifically after ECL, administration of a non-selective MMP inhibitor was able to diminish sprouting and synaptogenesis in the dentate OML , suggesting a direct proteolytic role for the MMPs in this process. In adults, most MMP expression and activity is low and maintained throughout adulthood. After injury and during the recovery and regenerative phase, however, there is increased activity of MMPs derived from glia and neurons that is thought to facilitate axonal reinnervation, sprouting and/or synaptogenesis. Nonetheless, the mechanism(s) of action of the MMPs and the potential substrates on which they act to promote neural plasticity have yet to be determined in these models. More recently, the activity and expression of the PG-degrading, ADAMTSs have been shown to be elevated in the OML after kainite-induced lesion. In contrast to the absence of a defined substrate for the MMPs, a selective ADAMTS-derived, brevican fragment was localized to the OML after seizure-induced lesion in the rat . In the present study, a similar ADAMTS-derived brevican fragment was localized to the OML of the mouse after discrete denervation of the perforant path, suggesting a critical role in neural plasticity for the proteolytic turnover of brevican. Thus, the ability to localize and quantitate the ADAMTS specific, proteolytic product of brevican provides a means to indirectly estimate ADAMTS activity during times of neural plasticity and synaptogenesis.
The expression of brevican was shown previously to be up-regulated in the OML, the area of denervation after ECL in the rat , however, in contrast to the transient production observed here in the mouse, expression of immunoreactive brevican remained elevated compared to the non-lesioned side for almost 6 months after injury. Neurocan is a lectican that is expressed at high levels during early development but it was found to be up-regulated and synthesized by astrocytes in the OML after ECL. It was suggested that neurocan and possibly brevican may act to maintain the boundary of the denervated dentate after ECL , yet these complex molecules may be multifunctional during periods of neural plasticity. Each of the lecticans, exhibit a characteristic pattern of expression during development, with neurocan and versican V1 highly expressed in the brain of the fetus and neonate, whereas aggrecan, versican V2 and brevican increase expression during the period of synaptic stabilization in the adult and expression remains high throughout adulthood [13, 31]. Each of the lecticans is thought to bind to tenascin R and hyaluronic acid (with varying affinities) forming a multi-molecular lattice of ECM . It may be that proteolytic cleavage of the lectican loosens the lattice to promote neurite growth and synaptogenesis. Classically, the highly negatively charged CS chains on the lecticans inhibits neurite outgrowth, but proteolytic cleavage of the core protein may allow more movement of these chains and actually promote plasticity of neurons. This is a testable notion and preliminary data indicates that the ADAMTSs promote neurite outgrowth and other measures of neural plasticity in vitro (our unpublished observations).
The projection from the EC to the hippocampus is called the perforant path , and is thought to be involved in long-term potentiation and learning and memory [33–35]. The ECL model to study neural and synaptic plasticity denervates up to 80% of the input to the outer two-thirds of the molecular layer of the dentate gyrus , and due to sprouting of surviving fiber systems will reinnervate nearly fully. This model was developed more than thirty years ago in the rat , yet it has been only relatively recently that the technique was employed in mice to take advantage of transgenic models [38, 39]. Surprisingly, there are some differences in the projections from the EC to the hippocampal formation between rats and mice . For example, input to the dentate molecular layer from the contralateral EC is absent in the mouse, yet these contralateral fibers are responsible for much of the sprouting after ECL in the rat. In addition, the width of the inner molecular layer, that contains associational-commissural fibers, is thinner in the mouse than in the rat, causing an increase in the relative width occupied by the middle and OMLs, layers innervated mainly by EC fibers. In the mouse, the middle and OML occupy closer to four-fifths of the total, rather than two-thirds as seen in the rat. Moreover, three layers can be clearly differentiated in an untreated mouse, but not in a rat, using synaptophysin immunohistochemistry , and following ECL this laminar feature is lost (Fig. 5B). Synaptophysin immunochemistry has been one of the more common techniques, among many, to quantitate the loss and reinnervation of input into the ipsilateral molecular layer of the dentate gyrus after unilateral ECL . Optical density of the synaptophysin signal in the contralateral OML is measured using the sum (or average) of the gray levels of the pixels in this region, and this value is used as a "normal" value to the ipsilateral side. However, with this technique, the ipsilateral dentate usually shows only a 10–30% reduction in signal compared to the contralateral side at seven days after lesion, a time when sprouting has begun . Clearly this absolute value does not reflect the extent to which fibers are actually lost in the OML after ECL. Thus, we decided to develop a fresh tissue, needle punch dissection technique that could be limited to the dentate gyrus in the mouse. This way, biochemical assays could be conducted on the tissue to measure overall synaptophysin immunoreactivity by ELISA. Using this method, at two and seven days after lesion, there was greater than a 40% reduction in synaptophysin levels in the OML, a value which at least may closer reflect the absolute loss of fibers after ECL. The major disadvantage of this method is that the dissected tissue also includes the granule layer and the hilus of the dentate, regions where input is not lost after ECL. At the same time using this technique, tissue containing the lesion itself may be collected and assayed biochemically or processed for histochemistry to monitor the extent of the lesion in the EC.
The present results suggest that the lecticans and the proteases that cleave the lecticans play a regulatory role in neural plasticity after ECL. There are several potential mechanisms by which this substrate – protease pair may modulate neural plasticity, one of which was described above. Significant changes were observed in the abundance of the different isoforms of brevican including the expression of the C-terminally-truncated ADAMTS-derived brevican fragment during plastic events in the hippocampus. A genetic approach to study the individual lecticans and ADAMTSs could reveal the individual contributions for each of the molecules involved in neural plasticity after ECL, however, there is considerable redundancy among these molecules. For example, there appears to be a compensatory increase in the expression of neurocan in the brain of the brevican null mouse.  In addition, several of the ADAMTSs exhibit proteoglycanase activity, and of these, at least ADAMTS1, 4 and 9 appear to be expressed in the nervous system (unpublished observations). Whether there are compensatory changes in the expression of any of these molecules in the brain in ADAMTS null mice remains to be determined. Nonetheless, significant protective effects toward arthritic changes were demonstrated just recently in a single mutant, the ADAMTS5 null mouse . Should it turn out that these proteases play a significant role in plasticity related mechanisms in the nervous system, it will be interesting to examine how removing this regulatory action will impact development, sprouting after lesion, learning and memory and other plasticity related mechanisms in the adult.
Growth, sprouting and targeting in neural plasticity of an ECL model may involve extracellular cues whose expression and/or secretion is altered following the lesion. One of these cues is the extracellular PG, brevican. Here we have demonstrated changes in brevican expression and turnover after ECL that are associated with the loss and time-dependent reinnervation of the OML of the dentate gyrus.
All animal procedures described here were approved by the Institutional Animal Care and Use Committee at the University of South Florida. Sixty-two adult male C57Bl6 mice (23 g – 27 g; Harlan, Indianapolis, IN), 12 weeks of age were housed under a 12 h light cycle with regulated temperature and humidity. Mice were housed 3 to 4 per cage and had free access to food and water. Following ECL surgery, the animals were housed individually. Brains from control mice (n = 4) and lesioned mice surviving for 2 days (n = 6), 7 days (n = 5) and 30 days (n = 5) after the lesion were perfusion fixed and collected for immunohistochemistry. Tissue extracts of dentate gyrus and EC lesioned animals collected 2 days (n = 6), 7 days (n = 5) and 30 days (n = 6) after surgery were used in Western blot and biochemical immunoassays. For those animals that received a unilateral ECL, the contralateral, non-lesioned hemisphere was considered the control for immunohistochemistry and biochemical analysis.
Surgical procedures – the entorhinal cortex lesion (ECL)
Surgeries were performed using isofluorane/oxygen mixed gas anesthesia. Once deeply anesthetized, animals were placed into the stereotaxic apparatus. A hole was drilled in the skull of the right hemisphere to allow for needle penetration. The right, lateral EC of mice was unilaterally lesioned by lowering a needle attached to a Hamilton syringe (#701N) filled with ibotenic acid through the hole in the skull to the coordinates AP = 4.72 mm, L = 3.75 mm and DV = 4.70 mm using bregma as a reference and oriented 17° rostral-caudal . One μl of the neurotoxin, ibotenic acid was injected into the lateral EC at a rate of 0.1 μl every 30 seconds, with the needle remaining in place for an additional minute at the end of the 5 min injection period to allow for complete diffusion of the drug into the lateral EC. Neurons of the lateral EC project preferentially to the septal dentate gyrus. The needle was removed, bone wax used to cover the skull hole, and the animal was allowed to recover on a heating pad after which the animal was returned to a new cage and housed individually. At 2, 7 and 30 days after lesion, mice were injected with an overdose of Nembutal (pentobarbital) for deep anesthesia, perfused transcardially with cold phosphate-buffered saline (pH 7.4) followed by cold 4% paraformaldehyde fixative diluted in 0.1 M phosphate buffer (pH 7.4). The brain was dissected from the skull, post-fixed in 4% paraformaldehyde overnight at 4°C, cryoprotected with consecutive solutions of 15 and 30% sucrose until completely infused, and the cryoprotected brain was sectioned on a cryostat at 30 μm. The extent and magnitude of the lesion in the EC was verified by cresyl violet and brevican staining. Synaptophysin and GFAP immunohistochemistry, using horseradish peroxidase amplification and diaminobenzidine as a chromogen, verified the loss of terminals in the molecular layer of the dentate gyrus.
Region isolation method
A method was developed to isolate dentate gyrus and EC tissue in mouse brain. This method eliminates the collection of much of the surrounding tissue that was unaffected by ECL. The dentate gyrus was subjected to synaptophysin ELISA as a measure of synaptic loss in the molecular layer. The EC underwent Western blot for PSD (post-synaptic density) 95 to quantitate the magnitude of the lesion. In addition, brevican and EAMESE Western blot was conducted on dentate gyrus tissue. Animals were completely anesthetized with a lethal dose of Nembutal (pentobarbital, Abbott Laboratories, North Chicago, IL), the brain was quickly removed and placed on a glass microscope slide, and a mm ruler was placed adjacent to the brain to assist in measuring the thickness of slices. Whole brain was dissected and frozen on a flat slab of dry ice for about 5 minutes (a point at which the brain surface is no longer shiny), being careful not to over-freeze the tissue, but to reach a temperature at which the tissue can be easily and efficiently cut into 2 mm coronal slabs. Two 2 mm coronal slabs are cut by referencing the most caudal of cerebral cortex as a land mark, making a coronal cut, moving rostrally 2 mm and making another cut to obtain the first slab for the EC isolation. A third cut was made 2 mm rostral from the previous slice and this slab contained the septal hippocampus and was used to isolate the dentate gyrus. The 2 mm hippocampal slab (outlined in Fig. 1C) was placed on a glass slide, and the dentate gyrus was localized using a stereomicroscope. The dentate was punctured with a blunt-ended 22 gauge needle (Fig. 1A) using the medial point of the wings as a landmark. A blunt-ended 18 gauge needle was used in the same manner to puncture and collect the EC from a 2 mm slab caudal to the slab used to collect the dentate gyrus (Fig. 1B). The frozen tissues were immediately expelled from the needle by attaching an air-loaded syringe to the needle and forcing the tissue into the bottom of a microfuge tube. The dentate gyrus and EC tissues were then homogenized in extraction buffer (20 nM Tris-HCL pH = 7.4, 5 mM EDTA, 1% Triton-X-100, & 1:100 protease inhibitor; 20 μl for dentate gyrus and 40 μl for EC) using three cycles of 2 min of 4°C incubation and 30 sec of vortex. The solubilized extract was centrifuged at 8000 rpm in a refrigerated microfuge for 3 min, the supernatant collected and frozen for later use in Western blotting and ELISA analysis.
Mice were anesthetized with an overdose of Nembutal (pentobarbital, Abbott Laboratories, North Chicago, IL) and their brains were fixed via standard cardiac perfusion methods. Briefly, the animal was cleared with phosphate buffered saline (PBS; pH 7.4) and fixed with 4% paraformaldehyde in 0.1 M phosphate buffer (PB; pH 7.4). The brains were post-fixed overnight in the same fixative; cryoprotected with 15% sucrose (in 0.1 M PB) followed by a 30% sucrose solution for 24 h each. Whole brain was frozen with mounting medium and cut into 30 μm coronal sections using a cryostat. Free-floating sections were washed with PBS, placed in a blocking/permeabilization solution (10% normal goat serum; 3% 1 M Lysine, 3% Triton-X) for 1 h, washed with PBS and incubated with primary antibody overnight at 4°C. For detection of the antigen, sections were washed and incubated in secondary antibody solution (anti-rabbit or anti-mouse IgG conjugated to Alexa-Fluor 488 or 594, Molecular Probes, Eugene, OR) for 1 h. The sections were washed for 15 minutes, wet mounted onto Fisher SuperFrost Plus glass sides and coverslipped with VectaShield mounting medium (Vector Labs, Burlingame, CA).
The primary antibodies or probes used in these experiments were: mouse anti-brevican, raised against the G1 domain of brevican (BD Transduction Labs, San Jose, CA); rabbit anti-EAMESE, the ADAMTS-derived neoepitope of brevican developed in our lab; rabbit anti-glial fibrillary acidic protein (GFAP, DAKO, Carpinteria, CA); and rabbit anti-synaptophysin (DAKO).
Dentate gryus or EC extracts were loaded (equal amounts of protein and 2 × sample buffer) on to 4–20% polyacrylamide gels (Invitrogen, Carlsbad, CA) and subjected to SDS-PAGE. Protein was transferred to a polyvinylidine difluoride membrane (PVDF, Immobilon, Millipore, Billerica, MA) and the membrane was blocked with 5% milk in PBS. Membranes were probed with primary antibodies against brevican (1:1000), EAM (1:500), and secondary anti-rabbit or anti-mouse IgG conjugated to horse radish peroxidase (Chemicon, Temecula, CA). Antigens were visualized using a chemiluminescence developing system (SuperSignal, Pierce, Rockford, IL).
A rabbit antibody raised against the brevican neoepitope on the 55 kD N-terminal fragment derived from glutamyl endopeptidase activity of the ADAMTSs was generated by Sigma-Genosys (St. Louis, MO) and purified in our laboratory. The novel C-terminal sequence "QEAMESE" from the mouse was the neoepitope and the peptide used for antibody generation contained a glycine spacer "GGGQEAMESE". This peptide was synthesized by Sigma-Genosys, conjugated to keyhole limpet hemocyanin at the N-terminus, and rabbits were subjected to standard immunization protocols. Serum collected after the 5th booster was titered against the peptide using a solid-phase system and specific antibody was purified using peptide affinity chromatography. Interestingly, antibody raised against the rat epitope "QEAVESE" did not recognize the mouse, ADAMTS-derived, "QEAMESE" epitope. On Western blot, the antibody against the mouse fragment recognized a single band at 55 kD in extracts from mouse brain and did not cross react with the intact brevican core protein.
The authors would like to acknowledge that this work was supported in part by Alzheimer's Association Grant IIRG-02-3758 and a grant from the Shriners Hospitals (research grant #8850). Dr. John Sandy (Shriners Hospital, Tampa, FL) was instrumental in the conceptual development of the neoepitope antibody.
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