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

J Clin Invest. 2021 Aug 16;131(16):e137221. doi: 10.1172/JCI137221.


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.

Keywords: Development; Epilepsy; Extracellular matrix; Neuroscience; Synapses.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA2 Region, Hippocampal / pathology
  • CA2 Region, Hippocampal / physiopathology*
  • Disease Models, Animal
  • Extracellular Matrix / pathology
  • Extracellular Matrix / physiology
  • Humans
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology
  • Male
  • Methyl-CpG-Binding Protein 2 / deficiency*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / physiology
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology
  • Neurons
  • Rett Syndrome / genetics
  • Rett Syndrome / pathology
  • Rett Syndrome / physiopathology*


  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2