Selective disruption of perineuronal nets in mice lacking Crtl1 is sufficient to make fear memories susceptible to erasure

Abstract

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals’ survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction.

Perineuronal nets and the neuronal extracellular matrix can be imaged by genetically encoded labeling of HAPLN1in vitroandin vivo

“…HAPLN1 is emerging as an important extracellular molecule implicated in memory, independent of our use as a target for genetically encoded labeling in the ECM. Disrupting PNNs in a HAPLN1 (Crtl1) mouse knock-out model rendered fear memories susceptible to erasure 44 . HAPLN1 turnover was found to be relatively rapid in PNNs and at synapses 45 , and viral-mediated HAPLN1 delivery into mouse cortex showed that HAPLN1 is both necessary for PNN maturation in mice and when overexpressed can accelerate PNN and memory engram formation 46 .…”

Hyaluronan hydrates and compartmentalises the CNS/PNS extracellular matrix and provides niche environments conducive to the optimisation of neuronal activity

“…The sulphation of GAGs is a key functional determinant in PNNs, changes in PG sulphation with ageing may render these structures more inhibitory (Fawcett & Kwok, 2022; Foscarin et al, 2017) and may be as a result of changes in the expression of sulphotransferases responsible for GAG sulphation (Properzi et al, 2008). Manipulation of PNNs has been proposed to be capable of altering selective memories (Poli et al, 2023; Romberg et al, 2013). PNNs have also been proposed to modulate visual inputs to the brain (Faini et al, 2018).…”

Novel extracellular matrix architecture on excitatory neurons revealed by HaloTag-HAPLN1

“…Notably, the ECM regulates plasticity and behavior [4][5][6][7]. Digestion of the main sugar modification on the major protein subunits of the ECM, chondroitin sulfate on chondroitin sulfate proteoglycans (CSPGs), with chondroitinase, restores juvenile levels of plasticity in a variety of paradigms, including ocular dominance plasticity, auditory learning, and fear memory consolidation [8][9][10][11]. Also, aged animals and animals in neurodegenerative models display increased memory performance after digestion of the ECM, overexpression of chondroitin-6-transferase, or ECM component knockouts [6,7,[12][13][14].…”