Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain.

Alessandro Venturino,Bálint Nagy,Mark F Bear,Rouven Schulz,Sandra Siegert,Francis Reilly-Andújar,Héctor De Jesús-Cortés,Florianne E Schoot Uiterkamp,Ryan John A Cubero,Margaret E Maes,Gloria Colombo

doi:10.1016/j.celrep.2021.109313

Alessandro Venturino, Bálint Nagy + Show 9 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109313

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Abstract

Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.

Highlights

Sensory processing is established through experience during the critical period of brain development (Hensch, 2005)
The end of that phase coincides with increased inhibition from fastspiking parvalbumin-positive (Pvalb+) neurons and the formation of the perineuronal net (PNN), a defined extracellular matrix (ECM) compartment consisting of chondroitin sulfate proteoglycans and various ECM and cell-adhesion molecules (Ueno et al, 2017a, 2018b)
Repeated ketamine exposure results in PNN loss To establish the consequences of ketamine exposure on PNNs, we subjected adult C57BL/6J animals to single or repeated ketamine anesthesia at 3-day intervals and collected the brains 4 h after one, two, three, or six injections (Figure 1A)

Summary

Introduction

Sensory processing is established through experience during the critical period of brain development (Hensch, 2005). Enzymatic digestion of the ECM with intracerebral application of chondroitinase ABC can reinstate juvenile-like plasticity in the adult cortex, but the enzyme uncontrollably degrades the ECM for several weeks and is not suitable for therapeutic interventions (Hensch, 2005; Pizzorusso et al, 2002). The application of ketamine at anesthetic dosage achieves the maximum pharmacological response with a consistent phenotypic readout across animals, avoiding the confounding effects of ketamine dosage, frequency, and time interval. This allowed us to address the underlying cellular mechanism involved in PNN reduction, which provides the fundaments to find alternative, non-invasive strategies to modify PNN in the healthy adult brain

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