Variation of chondroitin sulfation as a mechanism of tuning neuroplasticity during development and vestibular compensation

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are major constituents of the extracellular matrix (ECM) in the brain. The sulfated glycoforms in perineuronal nets around key interneurons were particularly attributed with roles of stabilizing the hardwired circuit. The corollary suggests tuning the sulfation pattern of perineuronal chondroitins as a way to re-open plasticity of the circuit. To address this, this study aimed (1) to determine the changes of CS sulfation in rat brains (i) as the neural circuitry matures during postnatal development and (ii) as the mature vestibular circuitry rewires during vestibular compensation and (2) to determine effects of model CSs that differ in sulfation pattern on the development of cortical neurons in culture. After establishing protocols of glycan extraction from brain tissues and high-performance liquid chromatography (HPLC)-based CS disaccharide separation, we found region-specific changes in the relative abundance of sulfated chondroitin moieties in the cerebral cortex and the brainstem during postnatal development. Examination of the functions of each CS moiety reported in the literature suggested that the changes likely bear functional significance. During the course of vestibular compensation following unilateral labyrinthectomy, real time PCR analysis of transcripts recovered from the vestibular nucleus revealed higher expression of chondro-sulfotransferases on the ipsilesional than the contralesional side at post-operation day 1; similar levels were observed on the two sides by day 3. Changes in the composition of CS moieties recovered from brainstem were reminiscent of those observed early in postnatal development. The growth of neurites on CS-A substratum was restricted but was not significantly affected on CS-C substratum. This indicates the different effects on neurite growth by chondroitins that differ in sulfation pattern. The results therefore support the hypothesis that the sulfation patterns of CS in the perineuronal environment are subject to activity-dependent modification so as to tune plasticity in a local circuits towards hardwiring for the specific sernsorimotor function.