Author:

Abstract:

Matrix metalloproteinases (MMPs) constitute a multifunctional endopeptidase family that is essential for normal brain development and neuroplasticity by acting on extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. One member, MMP-3 has recently been implicated in synaptic plasticity, neuronal development and differentiation. However, the function of this enzyme in development and plasticity of the sensory neocortex remains understudied and therefore we characterized the visual cortex of MMP-3 deficient (MMP-3-/-) mice on an anatomical, molecular and functional level. Golgi-Cox staining revealed a significant reduction in apical dendritic length and dendritic spine length, as well as an increase in apical oblique number of layer V pyramidal neurons. In addition, MMP-3-/- mice displayed a significant upregulation of all known neurofilament protein subunits, indicative for aberrant cytoskeletal dynamics. Collapsin response mediator protein-5 (CRMP-5), a critical determinant for dendritic outgrowth was upregulated, thus further substantiating the aberrant dendritic patterning. To evaluate a possible role for CRMP-mediated changes in autophagy and mitophagy we observed an upregulation of LC3-II, a marker for autophagy, but no changes in Mfn-2 and Drp1, markers for mitochondrial fusion and fission respectively. Taken together, these data hint at a possible CRMP-mediated autophagy mechanism underlying the observed dendritic phenotype. To assess the effect of MMP-3 deficiency on cortical plasticity, adult mice were monocularly enucleated and analyzed for zif268-based recovery of neuronal activity in the contralateral visual cortex seven weeks post-enucleation. Neural activity was confined to the binocular zone and did not expand into the monocular regions, indicative for an aberrant open-eye potentiation. The permanent hypoactivity in the monocular cortex lateral and medial to V1 suggests a lack of cross-modal plasticity. Together, these observations corroborate that genetic removal of MMP-3 has profound effects on the structural and functional integrity of neurons, lasting into adulthood.