Activity-Dependent Local Translation of Matrix Metalloproteinase-9

Abstract

Local, synaptic synthesis of new proteins in response to neuronal stimulation plays a key role in the regulation of synaptic morphogenesis. Recent studies indicate that matrix metalloproteinase-9 (MMP-9), an endopeptidase that regulates the pericellular environment through cleavage of its protein components, plays a critical role in regulation of spine morphology and synaptic plasticity. Here, we sought to determine whether MMP-9 mRNA is transported to dendrites for local translation and protein release. First, dendritic transport of MMP-9 mRNA was seen in primary hippocampal neuronal cultures treated with glutamate and in dentate gyrus granule cells in adult anesthetized rats after induction of long-term potentiation. Second, rapid, activity-dependent polyadenylation of MMP-9 mRNA; association of the mRNA with actively translating polysomes; and de novo MMP-9 protein synthesis were obtained in synaptoneurosomes isolated from rat hippocampus. Third, glutamate stimulation of cultured hippocampal neurons evoked a rapid (in minutes) increase in MMP-9 activity, as measured by cleavage of its native substrate, ␤-dystroglycan. This activity was reduced by the polyadenylation inhibitor, thus linking MMP-9 translation with protein function. In aggregate, our findings show that MMP-9 mRNA is transported to dendrites and locally translated and that the protein is released in an activity-dependent manner. Acting in concert with other dendritically synthesized proteins, locally secreted MMP-9 may contribute to the structural and functional plasticity of the activated synapses.

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

“…However, it is well established that expression of proteins may also be regulated at the posttranscriptional level. Also, it has been recently shown that MMP-9 mRNA can be transported to dendrites and undergo local translation in response to enhanced neuronal activity (58). Altogether, these results suggest the important role of both transcriptional and posttranscriptional regulation of MMP-9 expression in neurons.…”

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

“…This process is located in the core of maturation and maintenance of neuronal connections and physiological levels of synaptic plasticity (61,62). It is also possible that, in its secreted form (63), Mirta22 interacts and interferes with neurotrophic or extracellular matrix factors known to mediate activity-dependent dendritic plasticity (64,65).…”

Very long-term memories may be stored in the pattern of holes in the perineuronal net

“…No other method currently offers such high spatiotemporal resolution and specificity for genetically designated proteins. Evidence has been presented that MMP-9 is locally translated in synaptoneurosomes (18) and up-regulated by gross pharmacological glutamatergic stimulation (18,21). Such observations would be greatly improved by using TimeSTAMP (72) to image nascent MMP-9 with higher spatiotemporal resolution (72) in acute slices or intact brain as a function of electrical stimulation or behavioral conditioning, respectively.…”

“…Much of the problem is because the experiments showing effects on in vivo behavior rely on disruptions of the PNN or its degradative enzymes with low spatial and temporal resolution, leaving the possibility that these molecules are merely permissive and not carriers of detailed information. Much higher-resolution experiments have been done in synaptoneurosomes, slices, or cultures [for example, showing that MMP-9 is locally translated (18) and rapidly secreted at synapses in response to activity (19)(20)(21), that MMP inhibitors prevent late-phase synaptic potentiation (16)(17)(18)(19)(20), and that local puffing of MMP-9 onto spines can provoke spine enlargement and synaptic potentiation (19)(20)(21)(22)], but such manipulations cannot yet be linked to specific behaviors or memories. New techniques will need to be developed to test the hypothesis that very longterm memories are stored in the pattern and size of holes in the PNN and that the holes are dynamically created or enlarged by the above-listed enzymes.…”

“…Synaptosomes may need exposure to chondroitinase to remove residual PNN. Also note that, unlike the PNN itself, the PNN-degrading enzymes are likely to be rapidly turning over, which was hinted by their acute up-regulation and local translation minutes after synaptic activation (18,19,21).…”