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

Abstract

Perineuronal nets (PNNs), are neuron-specific substructures within the neural extracellular matrix (ECM). These reticular structures form on a very small subset of neurons in the central nervous system (CNS) and yet have a profound impact in regulating neuronal development and physiology. PNNs are well-established as key regulators of plasticity in the CNS. Their appearance coincides with the developmental transition of the brain more to less plastic state. And, importantly, numerous studies have demonstrated that indeed PNNs play a primary role in regulating this transition. There is, however, a growing literature implicating PNNs in numerous roles in neural physiology beyond their role in regulating developmental plasticity. Accordingly, numerous studies have shown PNNs are altered in a variety of neurological and neuropsychiatric diseases, linking them to these conditions. Despite the growing interest in PNNs, the mechanisms by which they modulate neural functions are poorly understood. We believe the limited mechanistic understanding of PNNs is derived from the fact that there are limited models, tools or techniques that specifically target PNNs in a cell-autonomous manner and without also disrupting the surrounding neural ECM. These limitations are primarily due to our incomplete understanding of PNN composition and structure. In particular, there is little understanding of the neuronal cell surface receptors that nucleate these structures on subset of neurons on which they form in the CNS. Therefore, the main focus our work is to identify the neuronal cell surface proteins critical for PNN formation and structure. In our previous studies we demonstrated PNN components are immobilized on the neuronal surface by two distinct mechanisms, one dependent on the hyaluronan backbone of PNNs and the other mediated by a complex formed by receptor protein tyrosine phosphatase zeta (RPTP{zeta}) and tenascin-R (Tnr). Here we first demonstrate that the Tnr-RPTP{zeta} complex in PNNs is bound to the cell surface by a glycosylphosphatidylinositol (GPI)-linked receptor protein. Using a biochemical and structural approach we demonstrate the GPI-linked protein critical for binding the Tnr-RPTP{zeta} complex in PNNs is contactin-1 (Cntn1). We further show the binding of this complex in PNNs by Cntn1 is critical for PNN structure. We believe identification of CNTN1 as a key cell-surface protein for PNN structure is a very significant step forward in our understanding of PNN formation and structure and will offer new strategies and targets to manipulate PNNs and better understand their function.