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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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 1

PNNs are increased in human RTT CA2 and develop prematurely in CA2 of a mouse model of RTT.

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PNNs are increased in human RTT CA2 and develop prematurely in CA2 of a ...
(A) Staining for the CA2-enriched protein RGS14 labels CA2 pyramidal neurons in control human hippocampal tissue in the stratum pyramidale (SP) and stratum radiatum (SR), but less in the stratum oriens (SO). Scale bars: 1 mm (top), 100 μm (bottom). (B) HAPLN1, a PNN link protein, is localized to area CA2 in a healthy human hippocampus (relative to background: CA1, 0.57; CA2, 1.67; CA3, 0.082). HAPLN1 appears greater in hippocampal tissue from an age- and sex-matched individual with RTT (relative to background: CA1, 1.06; CA2, 2.87; CA3, 0.52). Scale bars: 1 mm (top), 100 μm (bottom). (C) Left: Staining for the PNN marker WFA (green) is greater in Mecp2-null CA2 compared with WT littermates throughout early postnatal development. Scale bars: 200 μm. (D) Normalized WFA fluorescence intensity was significantly greater in Mecp2-null CA2 (n = 4, 4, 5 for ages P14, P21, P45, respectively) compared with WT littermates (n = 4, 3, 5 for ages P14, P21, P45, respectively); **P = 0.004, ****P < 0.0001, 2-way ANOVA, Bonferroni’s post hoc test, significant main effects of age F2,19 = 194.8, condition F1,19 = 110.5, and interaction F2,19 = 4.913. Indicated are means ± SEM. In addition, WFA staining surrounding PNN+ neurons in CA1 and CA3 did not differ between Mecp2-null males and WT littermates; P > 0.05, 2-way ANOVA. Indicated are means ± SEM. (E) Staining intensity for WFA (green) is greater in area CA2 of Mecp2-null at P11 compared with WT littermate. The CA2 pyramidal neuron borders with areas CA1 and CA3 are represented with white lines. Scale bars: 200 μm. (F) Normalized WFA fluorescence intensity was significantly greater in CA2 of P11 of Mecp2-null; ***P = 0.0005, 2-tailed unpaired t test (n = 9 and 5, WT littermate and Mecp2-null, respectively). Indicated are means ± SEM. Fluorescence intensity was amplified by camera exposure settings relative to exposure settings in C for quantification purposes.