Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
Kelly E. Carstens, … , Georgia M. Alexander, Serena M. Dudek
Kelly E. Carstens, … , Georgia M. Alexander, Serena M. Dudek
Published July 6, 2021
Citation Information: J Clin Invest. 2021;131(16):e137221. https://doi.org/10.1172/JCI137221.
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Research Article Development Neuroscience

Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome

Abstract

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provide evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8–11) in wild-type mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrate that CA2 PNN development is regulated by Mecp2 and identify a window of hippocampal plasticity that is disrupted in a mouse model of RTT.

Authors

Kelly E. Carstens, Daniel J. Lustberg, Emma K. Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek

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Figure 5

Loss of Mecp2 alters the molecular profile of the developing hippocampus.

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Loss of Mecp2 alters the molecular profile of the developing hippocampus...
(A) Given the premature loss of plasticity in Mecp2-null P8–11 mice, we examined gene expression differences at P10 and P18 in Mecp2-null compared with WT littermate control. Of the CA2-enriched genes (green font), Pcp4 and Spink8 were significantly lower in Mecp2-null compared with WT littermates (both unadjusted P value = 0.00730 and P = 0.0487, respectively). The CA2-enriched gene Fgf2 was significantly higher at both P10 (unadjusted P = 0.0101) and P18 (adjusted P = 0.0146). The inhibitory marker Gad1 was also significantly lower at P10 in Mecp2-null compared with WT (unadjusted P = 0.0332). Neither Rgs14 nor Acan (aggrecan) increased despite the increase in protein levels at P11 (Supplemental Figure 3A). We report no significant difference in the gene encoding PV (Parv), but note that the pattern of fold-change differences comparing Mecp2-null and WT depends on age. Genes with an adjusted P value less than 0.05 are designated with an asterisk, and genes with an unadjusted P value less than 0.05 are designated with “#”. Differences are presented as log2 fold change compared with WT littermates. (B) The endogenous ECM-degrading enzyme matrix metalloproteinase 9 (MMP-9) is significantly decreased in a hippocampal lysate of Mecp2-null males compared with WT littermates (P45–60); ***P = 0.0005, unpaired 2-tailed t test (n = 6 for P37–42 for Mecp2-null males and for WT littermates). Right: MMP-9 band intensity from Mecp2-null males was normalized to β-actin band intensity and divided by the average of the values from WT littermates. See complete unedited blots in the supplemental material.