Otx2 Binding to Perineuronal Nets Persistently Regulates Plasticity in the Mature Visual Cortex

Abstract

Specific transfer of Otx2 homeoprotein into GABAergic interneurons expressing parvalbumin (PV) is necessary and sufficient to open, then close, a critical period (CP) of plasticity in the developing mouse visual cortex. The accumulation of endogenous Otx2 in PV-cells suggests the presence of specific Otx2 binding sites. Here, we find that perineuronal nets (PNNs) on the surface of PV-cells permit the specific, constitutive capture of Otx2. We identify a 15 amino-acid domain containing an arginine-lysine doublet (RK-peptide) within Otx2, bearing prototypic traits of a glycosaminoglycan (GAG) binding sequence that mediates Otx2 binding to PNNs and specifically Chondroitin sulfate D and E with high affinity. Accordingly, PNN hydrolysis by Chondroitinase ABC reduces the amount of endogenous Otx2 in PV-cells. Direct infusion of RK-peptide similarly disrupts endogenous Otx2 localization to PV-cells, reduces PV and PNN expression and reopens plasticity in adult mice. The closure of one eye during this transient window reduces cortical acuity and is specific to the RK motif, as an AA variant or scrambled peptide fail to reactivate plasticity. Conversely, this transient reopening of plasticity in the adult restores binocular vision in amblyopic mice. Thus, one function of PNNs is to facilitate the persistent internalization of Otx2 by PV-cells to maintain CP closure. The pharmacological use of the Otx2 GAG-binding domain offers a novel, potent therapeutic tool with which to restore cortical plasticity in the mature brain.

Postnatal signalling with homeoprotein transcription factors

“…Indeed, closing an eye following either protocol can install amblyopia in the adult mouse and, more interestingly, the same protocols restore visual acuity and binocular vision in amblyopic mice [9,30]. Interestingly, reactivation of plasticity was also obtained by hydrolysing the complex sugars present in PNNs [33].…”

“…The glycosaminoglycans (GAGs) present in the PNNs serve as binding sites for Otx2 as demonstrated by genetic studies [31] and by the identification of a short Otx2 sequence (RKQRRERTTF-TRAQL) that specifically recognizes the GAGs expressed by PV cells [9]. Otx2 accumulation in PV cells permits the opening (first concentration threshold) and closing (second threshold) of a CP for binocular vision.…”

“…For example, HPs can interact with mRNA and regulate translation [6]. HPs typically have numerous binding domains and regulatory motifs outside the HD that allow interaction with not only other transcription factors but also translation factors, such as eIF4E [7], and many other molecules that are part of signalling pathways, such as kinases [8] or even complex sugars [9]. A recent review on Hox proteins attests to the reach of HP regulation, as they are implicated in DNA transcription, repair, initiation and replication, mRNA translation and signal transduction [10].…”

The role of epigenetic-related codes in neurocomputation: dynamic hardware in the brain

“…Continuous accumulation of Otx2 in PV cells may be necessary to sustain a state that limits further plasticity in the adult [8]. When this supply is cut off by deafferentation, and replaced by an input belonging to another sensory modality, this may allow the cell to undergo plastic changes organized perhaps by a new modality specific homeoprotein carried by the new input.…”

“…Over the past decade, this focus has greatly expanded with the discovery of the role that exosomes and their cargoes play in neuronal function [4][5][6], and the role that homeoproteins play in the adult brain [7][8][9][10]. We are now beginning to appreciate the possibility that the presynaptic neuron, via homeoproteins and exosomes, may change the internal computational machinery of the postsynaptic neuron by epigenetic-related mechanisms in remarkable ways.…”