Atypical perineuronal nets in the CA2 region interfere with social memory in a mouse model of social dysfunction

• Published in: Molecular psychiatry 2022-08, Vol.27 (8), p.3520-3531
• Main Authors: Cope, Elise C., Zych, Anna D., Katchur, Nicole J., Waters, Renée C., Laham, Blake J., Diethorn, Emma J., Park, Christin Y., Meara, William R., Gould, Elizabeth
• Format: Article
• Language: English
• Subjects: 14; 14/1; 14/19; 631/378; 64; 692/699/476/1373; Alzheimer's disease; Animals; Astrocytes; Axons; Behavioral Sciences; Biological Psychology; Dendritic spines; Dentate gyrus; Enzymes; Extracellular Matrix; Glial cells; Granule cells; Hippocampus; Inbreeding; Investigations; Medicine; Medicine & Public Health; Memory; Mental disorders; Mice; Mice, Inbred C57BL; Microglia; Nets; Neuroglia; Neuronal-glial interactions; Neurons - physiology; Neurosciences; Perineuronal nets; Pharmacotherapy; Psychiatry; Pyramidal Cells - physiology; Social interaction
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01174-2

Social memory dysfunction is an especially devastating symptom of many neuropsychiatric disorders, which makes understanding the cellular and molecular processes that contribute to such abnormalities important. Evidence suggests that the hippocampus, particularly the CA2 region, plays an important role in social memory. We sought to identify potential mechanisms of social memory dysfunction in the hippocampus by investigating features of neurons, glia, and the extracellular matrix (ECM) of BTBR mice, an inbred mouse strain with deficient social memory. The CA2 is known to receive inputs from dentate gyrus adult-born granule cells (abGCs), neurons known to participate in social memory, so we examined this cell population and found fewer abGCs, as well as fewer axons from abGCs in the CA2 of BTBR mice compared to controls. We also found that BTBR mice had fewer pyramidal cell dendritic spines, in addition to fewer microglia and astrocytes, in the CA2 compared to controls. Along with diminished neuronal and glial elements, we found atypical perineuronal nets (PNNs), specialized ECM structures that regulate plasticity, in the CA2 of BTBR mice. By diminishing PNNs in the CA2 of BTBR mice to control levels, we observed a partial restoration of social memory. Our findings suggest that the CA2 region of BTBR mice exhibits multiple cellular and extracellular abnormalities and identify atypical PNNs as one mechanism producing social memory dysfunction, although the contribution of reduced abGC afferents, pyramidal cell dendritic spine, and glial cell numbers remains unexplored.