Chondroitin 4- O -sulfation regulates hippocampal perineuronal nets and social memory

Abstract

Glycan alterations are associated with aging, neuropsychiatric, and neurodegenerative diseases, although the contributions of specific glycan structures to emotion and cognitive functions remain largely unknown. Here, we used a combination of chemistry and neurobiology to show that 4- O -sulfated chondroitin sulfate (CS) polysaccharides are critical regulators of perineuronal nets (PNNs) and synapse development in the mouse hippocampus, thereby affecting anxiety and cognitive abilities such as social memory. Brain-specific deletion of CS 4- O -sulfation in mice increased PNN densities in the area CA2 (cornu ammonis 2), leading to imbalanced excitatory-to-inhibitory synaptic ratios, reduced CREB activation, elevated anxiety, and social memory dysfunction. The impairments in PNN densities, CREB activity, and social memory were recapitulated by selective ablation of CS 4- O -sulfation in the CA2 region during adulthood. Notably, enzymatic pruning of the excess PNNs reduced anxiety levels and restored social memory, while chemical manipulation of CS 4- O -sulfation levels reversibly modulated PNN densities surrounding hippocampal neurons and the balance of excitatory and inhibitory synapses. These findings reveal key roles for CS 4- O -sulfation in adult brain plasticity, social memory, and anxiety regulation, and they suggest that targeting CS 4- O -sulfation may represent a strategy to address neuropsychiatric and neurodegenerative diseases associated with social cognitive dysfunction.

Mapping Extracellular Space Features of Viral Encephalitis to Evaluate the Proficiency of Anti‐Viral Drugs

“…To determine that the increased ECS diffusion observed after JEV infection was mainly caused by hyaluronic acid, we analyzed chondroitin sulfate proteoglycans (CSPGs), another constituent of the ECM, and showed that JEV infestation did not result in degradation of CSPGs, as evidenced by staining of wisteria floribunda agglutinin (Figure S2g, Supporting Information). [ 15,27 ] Further, we injected hyaluronidase (Hyase) into the mouse brain to study the morphological changes in the ECS (Figure 3e). Immunofluorescence experiments showed that HA in Hyase‐treated brains exhibited structural damage similar to that after JEV infection, with a significant reduction in HA content and smaller size (Figure 3f–h).…”

Influence of chondroitin sulfate glycan sulfation patterns on histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain

“…Notably, overexpression of chondroitin 6-sulfotransferase-1 (C6ST-1) in PV interneurons restricts the formation of stable PNNs and prevents binding of Otx2, resulting in aberrant maturation of PV interneurons and persistent cortical plasticity into adulthood (Miyata et al, 2012). Conversely, specific deletion of the chondroitin 4-sulfotransferase (C4ST-1) gene Chst11 in mice leads to an augmentation of PNNs in CA2 of the hippocampus (Huang et al, 2023).…”