Up-regulation of matrix metallopeptidase 12 in motor neurons undergoing synaptic stripping

• Upregulation of matrix metalloproteinase MMP12 in regenerating motor neurons.
• Neuronal MMP12 expression precedes peak of experimentally induced synaptic.
• Neuronal MMP12 becomes localized beneath the neuronal somatic membrane.
• A role for MMP12 in the neuronal initiation of the synaptic stripping process is suggested.
• Interference with synaptic stability may explain CNS side effects of statins.

Axotomy of the rodent facial nerve represents a well-established model of synaptic plasticity. Post-traumatic “synaptic stripping” was originally discovered in this system. We report upregulation of matrix metalloproteinase MMP12 in regenerating motor neurons of the mouse and rat facial nucleus. Matrix metalloproteinases (matrix metallopeptidases, MMPs) are zinc-binding proteases capable of degrading components of the extracellular matrix and of regulating extracellular signaling networks including within synapses. MMP12 protein expression in facial motor neurons was enhanced following axotomy and peaked at day 3 after the operation. The peak of neuronal MMP12 expression preceded the peak of experimentally induced synaptic plasticity. At the same time, MMP12 redistributed intracellularly and became predominantly localized beneath the neuronal somatic cytoplasmic membrane. Both findings point to a role of MMP12 in the neuronal initiation of the synaptic stripping process. MMP12 is the first candidate molecule for such a trigger function and has potential as a therapeutic target. Moreover, since statins have been shown to increase the expression of MMP12, interference with synaptic stability may represent one mechanism by which these widely used drugs exert their side effects on higher CNS functions.