Contactin-1 is a critical neuronal cell surface receptor for perineuronal net structure.

Perineuronal nets (PNNs) are neuron-specific, mesh-like, substructures within the central nervous system extracellular matrix. They form on specific subsets of neurons and are well-established as key regulators of plasticity. The appearance of PNNs coincides with the developmental transition of the brain from a more to less plastic state with numerous studies implicating PNNs in regulating this transition. Additionally, recent work has also linked PNNs to several neuropsychiatric and neurodevelopmental disorders. However, despite this growing interest in PNNs, the mechanisms by which they modulate neural functions are poorly understood. This limited mechanistic understanding of PNNs is derived from the fact that there are limited models, tools, or techniques that specifically target PNNs without disrupting the surrounding neural extracellular matrix. Our work, therefore, focuses on understanding how PNNs form on the surface of cells with the ultimate goal of developing models and tools to manipulate and disrupt PNNs specifically. Here, using a phosphatidylinositol specific phospholipase-C, we first demonstrate that PNN components are bound to the cell surface by a glycosylphosphatidylinositol-linked receptor protein. Furthermore, we demonstrate, through the exogenous addition of WT and a mutant variant of phoshpacan to primary cortical neurons, that contactin-1 is the glycosylphosphatidylinositol-linked protein critical for retaining nets to the cell surface. We believe the identification of contactin-1 as a key cell-surface protein for PNN structure is a very significant step forward in our understanding of the formation and structure of nets. It will offer new strategies to dissect the assembly of this specialized neural matrix.