%0 Journal Article
%T Chondroitin 4-O-sulfation regulates hippocampal perineuronal nets and social memory.
%A Huang H
%A Joffrin AM
%A Zhao Y
%A Miller GM
%A Zhang GC
%A Oka Y
%A Hsieh-Wilson LC
%J Proc Natl Acad Sci U S A
%V 120
%N 24
%D 2023 06 13
%M 37279269
%F 12.779
%R 10.1073/pnas.2301312120
%X 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.