Making the wrong connections in epilepsy

A matrix enzyme that helps us learn and remember might also promote epilepsy, as Wilczynski et al. report. The enzyme might clear the way for abnormal links between brain cells.Figure 1Fewer brain synapses sprout after treatment with an MMP-9 inhibitor (left) than in a control (right).Researchers think that epileptic seizures are the result of aberrant synapses between neurons that create stimulatory circuits. However, the rearrangement of neural circuits, known as synaptic plasticity, also allows learning and memory. Recent studies have shown that the enzyme matrix metalloproteinase 9 (MMP-9), which dissolves the extracellular matrix, is essential for synaptic plasticity. Wilczynski et al. wanted to determine whether MMP-9 also helps spur epilepsy. The researchers gave rodents either of two drugs that trigger epilepsy. Mice lacking MMP-9 were less likely to start having seizures than were control animals, and their attacks were less severe. The team then tested a line of genetically modified rats they had developed that pump out extra amounts of MMP-9. These rodents were particularly susceptible to seizures. Two types of synaptic plasticity occurred in mice that made MMP-9. First, the short spines that protrude from dendrites withered. Their shrinkage might open space for new synapses, the researchers speculate. Second, axons sprouted outgrowths called mossy fibers that link up with other cells. MMP-9's absence inhibited both types of plasticity, the researchers found. The work indicates that MMP-9 helps provoke epileptic seizures, possibly by rebuilding the extracellular matrix so that neurons can form new connections. MMP-9 is in the right place to perform that job, the team found: it accumulates at brain synapses. The results raise the possibility that drugs to block metalloproteinases, which are under development as cancer treatments, might also work against epilepsy. Reference: Wilczynski, G.M., et al. 2008. J. Cell Biol. 180:1021–1035. [PubMed]