Enzymatic Degradation of Cortical Perineuronal Nets Reverses GABAergic Interneuron Maturation

Abstract

Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical period of cortical plasticity. We have previously demonstrated that BDNF accelerates interneuron development in a c-Jun-NH2-terminal kinase (JNK)–dependent manner, which may involve upstream thousand-and-one amino acid kinase 2 (TAOK2). Chondroitinase-ABC (ChABC) enzymatic digestion of PNNs reportedly reactivates ‘juvenile-like’ plasticity in the adult CNS. However, the mechanisms involved are unclear. We show that ChABC produces an immature molecular phenotype in cultured cortical neurons, corresponding to the phenotype prior to critical period closure. ChABC produced different patterns of PNN-related, GABAergic and immediate early (IE) gene expression than well-characterised modulators of mature plasticity and network activity (GABAA-R antagonist, bicuculline, and sodium-channel blocker, tetrodotoxin (TTX)). ChABC downregulated JNK activity, while this was upregulated by bicuculline. Bicuculline, but not ChABC, upregulated Bdnf expression and ERK activity. Furthermore, we found that BDNF upregulation of semaphorin-3A and IE genes was TAOK mediated. Our data suggest that ChABC heightens structural flexibility and network disinhibition, potentially contributing to ‘juvenile-like’ plasticity. The molecular phenotype appears to be distinct from heightened mature synaptic plasticity and could relate to JNK signalling. Finally, we highlight that BDNF regulation of plasticity and PNNs involves TAOK signalling.

Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

“…One of underlying mechanisms seems to be mediated by the reduction in expression of PV and Kcnc1/Kv3, the potassium channels important for fast-spiking of PV neurons. Previous studies have reported similar changes after PNN degradation by chondroitinase ABC (Willis et al, 2022;Lupori et al, 2023).…”

Perinatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography

“…Depletion of CSPGs in the adult brain by enzymatic degradation or genetic inhibition has been shown to promote plasticity. [72][73][74] CSPGs can also act as potent inhibitors of myelination, axon guidance and regeneration, and other injury repair processes. Further work is needed to determine the clinical relevance of CSPGs in myelin recovery after perinatal WMI.…”

Influence of Chronic Electroconvulsive Seizures on Plasticity-Associated Gene Expression and Perineuronal Nets Within the Hippocampi of Young Adult and Middle-Aged Sprague-Dawley Rats

“…A hallmark cellular feature associated with the closure of critical periods is the deposition of PNNs ( Pizzorusso et al, 2002 ), which are lattice-like, proteoglycan-rich, ECM structures that coalesce around specific neuronal populations, in particular PV + inhibitory interneurons, and are linked to the limiting of neuronal plasticity in mature neuronal networks ( Bozzelli et al, 2018 ; Sigal et al, 2019 ; Willis et al, 2022 ). Prior evidence indicates that pharmacological antidepressants reopen “critical period-like plasticity” in adulthood, likely via the recruitment of Tropomyosin receptor kinase B (TrkB) signaling in PV + interneurons ( Maya Vetencourt et al, 2008 ; Guirado et al, 2014 ; Lesnikova et al, 2021 ; Mukhopadhyay et al, 2021 ).…”