Swish!—All I Hear is Net—Perineuronal Net That is!

Contribution of Perineuronal Nets to Hyperexcitability in Pilocarpine-Induced Status Epilepticus Woo AM, Fleischel EJ, Patel DC, Sontheimer H. Epilepsia 2025;66(9):3528–3543. Objective: Changes in extracellular matrix (ECM) and highly condensed ECM structures called perineuronal nets (PNNs) have been reported in human patients with epilepsy as well as some animal models of epilepsy. We studied potential ECM changes in a mouse model of pilocarpine-induced status epilepticus (PISE) and their potential contributions to seizures. Methods: We used a reduced intensity pilocarpine model to induce status epilepticus (SE) in mice. Wisteria floribunda agglutinin (WFA) staining was used to identify PNNs. Immunohistochemistry, patch-clamp electrophysiology, drug studies, and transcriptomic analysis were used to assess changes in gene expression and physiological properties of the PNN-surrounded cells. Results: WFA immunohistochemical staining shows de novo synthesis of PNNs around a heterogeneous population of interneurons, suggesting both inhibitory and disinhibitory neurons acquired PNNs post-SE. Patch-clamp electrophysiology from these cells indicates hyperexcitability in PNN-bearing neurons in PISE mice, without a change in intrinsic cell properties except for afterhyperpolarization. Enzymatic degradation of PNNs partially rescued hyperexcitability but did not fully reverse it, suggesting that PNNs are at least in part necessary for the observed hyperexcitability. Other likely contributors include changes in ion channels that underlie afterhyperpolarization (eg, K + channels). We investigated candidate channels using channel-specific pharmacological blockers, but with inconclusive results. However, transcriptomic data show upregulation of a K + channel gene, Kcnk6, as well as genes for ECM-remodeling enzymes and numerous immune-associated genes. Significance: De novo formation of PNNs around interneurons in the CA1 region contributes to hyperexcitability of the cells they surround. This acquisition of PNNs is associated with a compensatory or causative mechanism occurring in the wake of PISE, with implications for PNNs in epileptogenesis and possibly other acquired forms of epilepsy.