, 2008). To date the target of MMP9 proteolysis within the ECM that induces integrin signaling remains unknown. Another matrix metalloprotease, MMP3, is able to process agrin at the basal lamina of the neuromuscular junction in an activity-dependent manner (Werle & VanSaun, 2003). It has been suggested that this process is responsible for fast removal of agrin from the neuromuscular junction, where it induces acetycholine receptor clustering and is indispensible for normal neuromuscular junction development (Sanes & Lichtman, 2001). In line with this view, MMP3-knockout mice exhibit Ganetespib molecular weight abnormal neuromuscular junction morphology and

acetylcholine receptor distribution (VanSaun et al., 2003). Another protease that has recently been found to act on agrin as its main substrate

is the brain-specific serine protease neurotrypsin (Reif et al., 2008). Neurotrypsin can be released at synapses in an activity-dependent manner where it locally see more processes agrin into distinct fragments (Frischknecht et al., 2008; Stephan et al., 2008). Interestingly, neurotrypsin has been identified as essential for cognitive function in the human brain (Molinari et al., 2002). In an elegant series of experiments it was demonstrated that the proteolytic fragment of 22 kDa acquired signaling properties that induced filopodia in hippocampal slice cultures after induction of synaptic long-term potentiation (Matsumoto-Miyai et al., 2009). Thus, similar to MMP9, proteolytic cleavage of ECM components unmasked a signaling molecule, Pyruvate dehydrogenase which in turn led to an altered spine morphology and even to the generation of new synapses. Hence, these examples demonstrate that the ECM contains a variety of hidden instructive signals that can be revealed by specific proteolysis. Finally, it has been demonstrated that, similar to chondroitinase ABC treatment, the topical application of the serine protease tissue-type

plasminogen activator (tPA) can prolong the so-called critical period in the visual cortex (Mataga et al., 2004; Oray et al., 2004). It was shown that tPA induces activity-dependent pruning of dendritic spines in the visual cortex. However, it is currently unclear whether pruning after tPA treatment depends on a newly generated signaling molecule, similar to the mode of action of neurotrypsin or MMP9, or whether the effect is based on the removal of the PNN-like structures as a general barrier for filopodial outgrowth (Berardi et al., 2004). The ECM protein reelin has also been discussed as a serine protease (Quattrocchi et al., 2002). In the adult CNS it mediates its function via binding to its cell surface receptors very-low-density lipoprotein receptor (VLDLR) and ApoE2 receptor (APOE2R) and the downstream adaptor protein Dab1.