Persistent cortical plasticity by upregulation of chondroitin 6-sulfation

Abstract

Cortical plasticity is most evident during a critical period in early life, but the mechanisms that restrict plasticity after the critical period are poorly understood. We found that a developmental increase in the 4-sulfation/6-sulfation (4S/6S) ratio of chondroitin sulfate proteoglycans (CSPGs), which are components of the brain extracellular matrix, leads to the termination of the critical period for ocular dominance plasticity in the mouse visual cortex. Condensation of CSPGs into perineuronal nets that enwrapped synaptic contacts on parvalbumin-expressing interneurons was prevented by cell-autonomous overexpression of chondroitin 6-sulfation, which maintains a low 4S/6S ratio. Furthermore, the increase in the 4S/6S ratio was required for the accumulation of Otx2, a homeoprotein that activates the development of parvalbumin-expressing interneurons, and for functional maturation of the electrophysiological properties of these cells. Our results indicate that the critical period for cortical plasticity is regulated by the 4S/6S ratio of CSPGs, which determines the maturation of parvalbumin-expressing interneurons.

Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

“…For example, altered sulfation of N-acetylgalactosamine (GalNAc, a major disaccharide found in CSPGs) results in greatly reduced WFA labeling (Miyata et al, 2012). Furthermore, PNNs might be subject to enhanced degradation in schizophrenia.…”

“…Third, the loss of ECM components increases the mobility of excitatory AMPA receptors (Frischknecht et al, 2009), potentially altering the ability of glutamatergic inputs to depolarize the cell. Fourth, disruption of PNNs can alter the resting membrane potential of PV neurons (Miyata et al, 2012) and decrease the amplitudes of both inhibitory (Liu et al, 2013) and excitatory (Pyka et al, 2011) postsynaptic currents. Each of these factors could affect the excitability of PV neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67 (Kimoto et al, 2014), in PV neurons.…”

“…Each of these factors could affect the excitability of PV neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67 (Kimoto et al, 2014), in PV neurons. Several studies suggest that ECM components, including PNNs, are critical regulators of synaptic plasticity Miyata et al, 2012;Morishita et al, 2015). Finally, PNNs appear to be both protective against and altered by high levels of oxidative stress (Cabungcal et al, 2013a;Do et al, 2015;Morishita et al, 2015).…”

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

“…The direct link with plasticity is stressed by the activity-regulated maturation of EM [5][6][7] ending in parallel with the closure of the juvenile critical period of heightened plasticity 6,8 . The relationship between critical period closure and EM is reciprocal, as alterations of the EM structure prolong the critical period 9,10 and plasticity processes can be partially restored in the adult brain by degradation of the EM [11][12][13][14][15] . Key components of the extracellular environment are the chondroitin sulfate proteoglycans (CSPGs): these molecules are formed by a proteic scaffold supporting chondroitin sulfate glycosaminoglycan chains.…”

Postnatal signalling with homeoprotein transcription factors

“…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.…”