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 3

Potentiation is prematurely restricted in CA2 of a mouse model of RTT via PNNs.

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Potentiation is prematurely restricted in CA2 of a mouse model of RTT vi...
(A) Potentiation failed to be induced at CA2 stratum radiatum synapses at ages P8–11 in acute hippocampal slices from Mecp2-null mice (red) compared with WT (black). Top: Representative EPSCs from Mecp2-null P8–11 CA2 neurons at baseline and 20 minutes after the LTP pairing protocol (post-stimulation). Right: Normalized mean response amplitudes 18–20 minutes after pairing; **P = 0.0031, 2-tailed unpaired t test (n = 14 and 13, WT littermate and Mecp2-null, respectively). (B) EPSC amplitudes in response to indicated stimulation current intensity were not different in Mecp2-null CA2 neurons compared with WT littermate at P8–11; main effect of genotype P = 0.2738, 2-way ANOVA, repeated-measures analysis, Šidák’s post hoc test (n = 9 and 5, WT littermate and Mecp2-null, respectively). Top: Representative traces from a Mecp2-null CA2 neuron at P8 in response to increasing stimulation intensities. (C) Paired-pulse ratio did not differ between Mecp2-null and WT CA2 synapses (S1, peak of first stimulus response; S2, peak of second stimulus response). Top: Representative traces using a 50-millisecond stimulus interval from a P11 Mecp2-null CA2 neuron; average of 4 responses. (D) Action potential firing frequency of Mecp2-null CA2 neurons did not differ in comparison with WT; P > 0.05, 2-way ANOVA (n = 12 and 18, WT and Mecp2-null, respectively). Top: Representative traces of action potentials from 0 to 180 pA current injection in a P8 Mecp2-null CA2 cell. (E) Degradation of PNNs by incubation of slices in vitro with chondroitinase ABC (ChABC) for 2 hours resulted in potentiation being restored. Top: Representative EPSCs from CA2 +ChABC Mecp2-null P8 neurons at baseline and 20 minutes after LTP pairing (post-stimulation). Right: Normalized mean response amplitudes at 18–20 minutes of recovery; *P = 0.035, 2-tailed unpaired t test (n = 14 and 10, Mecp2-null and +ChABC Mecp2-null, respectively).