Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome
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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.
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Both hippocampus and perirhinal cortex are rich in PV interneurons enwrapped with PNNs, and PNNs are also present on some hippocampal pyramidal neurons.
“Both hippocampus and perirhinal cortex are rich in PV interneurons enwrapped with PNNs, and PNNs are also present on some hippocampal pyramidal neurons [46, 101, 102].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [102]
Rett syndrome is associated with larger denser PNNs around PV interneurons in the cortex and many neurons in hippocampal CA2, possibly due to decreased secretion of MMP-9.
“The condition is associated with larger denser PNNs around PV interneurons in the cortex and many neurons in hippocampal CA2 (which mediates social behaviours), possibly due to decreased secretion of the metalloproteinase MMP-9.”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [102]
In a Rett syndrome model, there is an increase in the number and complexity of PNNs around PV interneurons in the cortex, altering cortical excitability.
“In the cortex there is also an increase in the number and complexity of PNNs around PV interneurons in a Rett syndrome model, altering cortical excitability [102, 180].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [102]
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The extracellular matrix and perineuronal nets in memory
Fawcett, J. W., Fyhn, M., Jendelova, P., Kwok, J. C. F., Ruzicka, J., & Sorg, B. A. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01634-3 · Cited by 169 · see citing works
- Authors
- Carstens, K. E., Lustberg, D. J., Shaughnessy, E. K., McCann, K. E., Alexander, G. M., & Dudek, S. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Dudek, Serena M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-08-16
- Volume
- 131
- Issue
- 16
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8363283
- OpenAlex
- W3181385353
- Cited by
- 57
- References
- 32
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 6 · 2023: 17 · 2022: 10 · 2021: 2
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (Z01 ES100221)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- perineuronal nets, Rett syndrome, Mecp2-null mice, hippocampal CA2, synaptic plasticity, long-term potentiation, extracellular matrix, social learning, neuronal activity regulation
- MeSH terms
- Animals, Disease Models, Animal, Extracellular Matrix, Humans, Male, Nerve Degeneration, Neuronal Plasticity, Neurons, Rett Syndrome, Long-Term Potentiation, Mice, Knockout, Mice, Methyl-CpG-Binding Protein 2, CA2 Region, Hippocampal
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