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 human brain of 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 reported that PNNs appear elevated in area CA2 of a human RTT hippocampus and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provided evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wildtype 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 demonstrated that CA2 PNN development is regulated by Mecp2 and identified a novel window of hippocampal plasticity that is disrupted in a mouse model of RTT.

Excitation and Inhibition Imbalance in Rett Syndrome

“…Maternal experience induces region-specific alteration of PNNs in WT but fails to do so in Mecp2 HET mice. Elevated levels of PNNs are also seen in hippocampal CA2 of Mecp2 KO mice (Bird line), which can be downregulated via chemogenetic reduction of neuronal activity (Carstens et al, 2021). This study further demonstrates that an extracellular matrix degrading enzyme matrix metalloproteinase (MMP) is reduced in Mecp2 KO mice, which may explain the increased expression of PNNs.…”

“…The impairment of LTP-like plasticity is also shown in the motor cortex of RTT patients, which favors cortical hyperexcitation as a result of GABAergic dysfunction (Bernardo et al, 2020). LTP in hippocampal CA2 of Mecp2 KO mice (Bird line) is disrupted due to enhanced expression of PNNs and can be rescued by degrading PNNs (Carstens et al, 2021). LTD is also affected in CA3 pyramidal neurons of Mecp2 KO mice (Bird line) because of the loss of developmental shift of GABAergic activity (Lozovaya et al, 2019).…”

Neurogenesis mediated plasticity is associated with reduced neuronal activity in CA1 during context fear memory retrieval

“…But how does postnatal neurogenesis in the DG impact PNN expression in CA1? Direct and/or local neuronal activity has previously been linked to modification of PNNs 44 – 46 . We hypothesized that the activity of postnatal-generated neurons could alter the circuit activity of the DG resulting in PNN changes in CA1.…”

How Stress Influences the Dynamic Plasticity of the Brain’s Extracellular Matrix

“…It should be recognized that outside of critical periods, PNNs are capable of rapid remodeling, as has been recently demonstrated in several studies (Marchand and Schwartz, 2020;Pantazopoulos et al, 2020;Uriarte et al, 2020). Evidence suggests that changes in PNNs can occur through alterations in neuronal activity both during development and in adulthood (Dityatev et al, 2007;Carstens et al, 2021;Devienne et al, 2021). Thus, stress-induced changes in neuronal activity (Della Valle et al, 2019;Murthy et al, 2019;Del Arco et al, 2020;Fee et al, 2020) could be a mechanism by which alterations in PNNs occur.…”