Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice

Abstract

The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.

Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9

“…In WT adults, LRx promoted a significant enhancement of non-deprived eye VEP following MD (between subjects repeated measures ANOVA, F (df,1,8) =6.33, p=0.026, MD n=12, MD+LRx n=8). However, we did not observe an increase in the strength of the non-deprived input in Mmp9 −/− mice, consistent with previous reports ( Spolidoro et al, 2012 ; Kelly et al, 2015 ; Pielecka-Fortuna et al, 2015 ) and observed no reactivation of the response to MD after LRx (between subjects repeated measures ANOVA F (df,1,5) =0.633, p=0.890; MD n=6, MD+LRx n=5; Figure 6A ). During the critical period for ocular dominance plasticity, MD induces a significant decrease in the density of dendritic spines on pyramidal neurons in deprived V1b (contralateral to the occlusion), but this plasticity is lost with age ( Mataga et al, 2004 ).…”

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress

“…Finally, the enrichment of DEGs that contribute to the ECM in the 5-week RTT samples is interesting in view of the contribution made by microglia, albeit modest compared with astrocytes and neurons, to ECM homeostasis [77–81]. Considering the importance of the ECM in maintaining synaptic function, the altered expression of ECM components and regulators in the pre-phenotypic phase could play some role in the synaptic dysfunction that ultimately leads to clinical symptoms.…”

Spike Timing-Dependent Plasticity in the Mouse Barrel Cortex Is Strongly Modulated by Sensory Learning and Depends on Activity of Matrix Metalloproteinase 9

“…Several lines of evidence indicate that especially MMP-9 and MMP-3 play a pivotal role in these processes [ 30 – 36 ]. More recently, it has been shown that in the cortex both MMPs are involved in learning and in the plasticity processes [ 36 – 39 ]. In particular, Kaliszewska et al [ 38 ] have shown that MMP-9 knockout resulted in a decreased plasticity in layer IV and II/III in barrel cortex of adult mice.…”