Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
Kelly E. Carstens, Daniel J. Lustberg, Emma K. Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek
Kelly E. Carstens, Daniel J. Lustberg, Emma K. Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek
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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 4

CA2 PNNs are inversely regulated by neuronal activity in vivo.

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CA2 PNNs are inversely regulated by neuronal activity in vivo. (A) Exper...
(A) Experimental timeline indicating the infusion of the DREADD-AAV into the hippocampus of Amigo2-iCreERT2+ and Amigo2-iCreERT2– mice. Two weeks later, tamoxifen injections were given for 7 days to induce selective expression in CA2 neurons. Two weeks after the last tamoxifen injection, the DREADD ligand CNO was given twice daily for 5 days (1 mg/kg for Gq DREADD, 5 mg/kg for Gi DREADD, s.c.). (B) Immunofluorescence shows mCherry-Gq DREADD (red) only in CA2 neurons. Representative images of WFA fluorescence intensity (green) in the hippocampus after 5 days of CNO treatment. Scale bars: 200 μm. (C) Quantification of WFA staining in CA2 showed a significant reduction in Gq DREADD–expressing animals compared with Cre– controls (*P = 0.011, unpaired 2-tailed t test; n = 4 and 5 for Cre– and Cre+, respectively) and increase in CA2 of Gi DREADD–expressing animals compared with Cre– controls (*P = 0.0179, unpaired 2-tailed t test; n = 6 for both Cre– and Cre+ groups). (D) Spontaneous electrographic seizures were detected in vivo in the hippocampus of a mouse model of epilepsy, the Kv1.1-null mouse. Examples of electrographic seizure activity detected by LFP recordings from the hippocampus during a 1-hour recording session in a P40 Kv1.1-null male mouse are shown. A period of non-ictal activity during the same recording session is shown for comparison. (E) Staining for PNN marker WFA (green) is reduced in CA2 of Kv1.1-null mice compared with WT littermates at P60. CA2 pyramidal neurons are identified with the CA2 marker PCP4 (red). Scale bars: 200 μm. (F) Normalized WFA fluorescence intensity was decreased at P45–60 in CA2 compared with WT; *P = 0.033 (n = 4, 4, 3, and 5 for ages P14, P22, P28, and P45, respectively). In contrast, WFA fluorescence intensity was significantly greater in the dentate gyrus (DG) of Kv1.1-null mice compared with WT littermates at P45–60; ***P = 0.0002, Bonferroni’s post hoc test for pairwise comparison after 2-way ANOVA. Indicated are means ± SEM normalized to P45 WT group.