**5. ECM proteolysis and the generation of synaptic signaling molecules**

Endogenous ECM-modulating enzymes regulate synaptic function in the juvenile and adult brain [25,26]. Such enzymes can exert their function by either altering the extracellular milieu via digestion of the ECM or by generating proteolytic fragments that may act as signaling molecules. An important group of such enzymes are the metalloproteases of the ADAMTSfamily (a disintegrin and metalloproteinase with thrombospondin motifs). Within this family, ADAMTS-4/-5 are particularly interesting, as they are known for their ability to digest aggrecan and brevican. Therefore, they have been termed previously aggrecanase-1/-2. The current terminology, however, better reflects the ability of these enzymes to digest all members of the lectican family. Interestingly, their activity is increased after epileptic seizures and regulates homeostatic plasticity [27]. However, their impact on synaptic plasticity remains elusive and is subject of current research. The best-studied extracellular protease is the matrix metalloprotease 9 (MMP9). The activity-dependent expression of MMP9 influences synaptic plasticity by regulating spine enlargement and synaptic potentiation [25]. Recently, a molec‐ ular signaling cascade regulating synaptic plasticity has been identified based on the MMP-9 dependent cleavage of neuroligin-1 [28]. This study has demonstrated that focal activation of a single spine by glutamate uncaging is sufficient to cleave neuroligin-1. Moreover, the activity of MMP9 has been shown to be NMDA-receptor dependent and hence implemented locally input-specific forms of synaptic plasticity. Thereby, extracellular MMP-9 triggers a specific retrograde regulation of presynaptic efficacy by targeting postsynaptic neuroligin-1 [26,28]. Similarly, the brain-specific serine protease neurotrypsin is regulated in an activity-dependent manner and requires concomitant activation of the postsynaptic neuron [29]. Proteolytic cleavage of agrin by neurotrypsin unmasks a signaling molecule harboring a single laminin G3 domain. This 22 kDa molecule can further regulate spine morphology and de-novo synapse generation. Together, this suggests that proteolysis of components of the ECM by exoenzymes not only modify the structural rigidity, but also activates instructive signal molecules that locally modulate synaptic functions [25]. This may temporally restore local divisions of "juvenile" environments as a major constituent of the balance between plasticity and tenacity in the mature brain.

We have shown that the ECM in the adult brain is a plastic structural scaffold shaped by network activity. Depending on the current activity level, the ECM can incorporate secreted components or release signaling messengers by proteolytic cleavage. Cleaved products can trigger signaling through diverse ECM receptors and modulate the activities of transmitter receptor, ion channels, or integrin signaling impacting on plastic shaping of individual synapses.
