Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.
Matrix metalloproteinase-9 has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. However, no synaptic targets for its enzymatic activity had been identified before. In this report, we show that -dystroglycan comprises such a neuronal activity-driven target for matrix metalloproteinase-9. This notion is based on the following observations. (i) Recombinant, autoactivating matrix metalloproteinase-9 produces limited proteolytic cleavage of -dystroglycan. (ii) In neuronal cultures, -dystroglycan proteolysis occurs in response to stimulation with either glutamate or bicuculline and is blocked by tissue inhibitor of metalloproteinases-1, a metalloproteinase inhibitor. (iii) -Dystroglycan degradation is also observed in the hippocampus in vivo in response to seizures but not in the matrix metalloproteinase-9 knock-out mice. (iv) -Dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, -dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the -dystroglycan as a first matrix metalloproteinase-9 substrate digested in response to enhanced synaptic activity. This demonstration may help to understand the possible role of both proteins in neuronal functions, especially in synaptic plasticity, learning, and memory. Matrix metalloproteinases (MMPs)2 are a family of zinc-dependent endopeptidases acting outside the cells and therefore attributed with digesting extracellular matrix components. These enzymes are produced in a latent form, and after release to extracellular space, they are activated by cleavage off the propeptide (1, 2). MMPs are involved in a number of physiological and pathological conditions, including development, tissue remodeling, inflammation, and tumor metastasis (1-4). Specifically, multiple data show increased expression and activity of MMPs after brain injury and in certain diseases of the central nervous system (5). On the other hand, the physiological roles of MMPs in the adult brain have only recently been appreciated (4). In particular, MMP-9 (also known as gelatinase B) has been implicated in synaptic plasticity, learning, and memory (6, 7). Furthermore, a marked increase in MMP-9 mRNA protein and its enzymatic activity in the hippocampal dentate gyrus after kainate-evoked seizures has been shown (8). Kainate, a glutamate analog, produces excitotoxicity in the CA subfields of the hippocampus, sparing the granule neurons of the dentate gyrus that, however, undergo aberrant plastic changes (9).Despite data implicating MMP-9 in neuronal/synaptic plasticity, no synaptic targets for its enzymatic activity have as yet been identified in neurons. However, recent studies have suggested that this enzyme may digest the 43-kDa -dystroglycan (-DG) to release a 30-kDa product from the full-length subunit. First, Yamada et al. (10) have shown that unidentified MMPs digest -DG to reveal the 30-kDa product in the perip...
Kynurenine is a small molecule derived from tryptophan when this amino acid is metabolised via the kynurenine pathway. The biological activity of kynurenine and its metabolites (kynurenines) is well recognised. Therefore, understanding the regulation of the subsequent biochemical reactions is essential for the design of therapeutic strategies which aim to interfere with the kynurenine pathway. However, kynurenine concentration in the body may not only be determined by the efficiency of kynurenine synthesis but also by the rate of kynurenine clearance. In this review, current knowledge about the mechanisms of kynurenine production and routes of its clearance is presented. In addition, the involvement of kynurenine and its metabolites in the biology of different T cell subsets (including Th17 cells and regulatory T cells) and neuronal cells is discussed.
Tryptophan is an essential amino acid which influences a wide range of physiological processes, including mood, cognition, and immunity. In the autoimmune diseases, such as rheumatoid arthritis (RA), the induction of tryptophan catabolism may help to diminish exacerbated immune responses. In this study, using collagen‐induced arthritis (CIA) in DBA/1 mice which is an animal model of RA, the endogenous activity of the kynurenine pathway in the immune system was monitored before and after onset of the disease. An increased rate of the initiation of tryptophan catabolism via the kynurenine pathway throughout CIA has been observed. However, decreased tryptophan concentration in the lymph nodes from pre‐arthritic mice was not enough to prevent development of CIA. In contrast, resolution of inflammation coincided with the decreased concentration of tryptophan and accumulation of its catabolites: kynurenine, anthranilic acid, and 3‐hydroxyanthranilic acid in lymph nodes but not in the spleen. In addition, the lack of the accumulation of kynurenine and its downstream metabolites in the pre‐arthritic lymph nodes coincided with increased mRNA expression for genes involved in the catabolism of kynurenine (Kynureninase, kynurenine 3‐monooxygenase, and 3‐hydroxyanthranilate 3,4 dioxygenase). However, in the lymph nodes from mice with established CIA, mRNA expression for these genes was normalized. Hence, keeping in mind an exploratory character of the results, it can be postulated that an anti‐inflammatory role of the kynurenine pathway reaches its full potential only when decreased concentration of tryptophan coincides with accumulation of kynurenines driven by metabolic regulation of gene expression on the kynurenine pathway. © 2012 IUBMB IUBMB Life, 64(12): 983–987, 2012
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