THE HYALURONAN EXTRACELLULAR MATRIX CRITICALLY REGULATES SYNAPSE FORMATION IN DEVELOPING NEURAL NETWORKS

Abstract

The majority of neurodevelopmental disorders present with an imbalance in synaptic signal transmission. The delicate balance of excitatory to inhibitory synaptic transmission is regulated by multiple extracellular and intracellular factors. Specifically, our work demonstrates that the major extracellular component of the brain, hyaluronan, critically regulates synaptic formation and the emerging balance between inhibitory and excitatory neurotransmission. Furthermore, our results suggest that these effects are in part mediated by hyaluronan's interaction with its receptor, CD44, leading to actin cytoskeleton rearrangements that alter synapse formation. For the first time, we demonstrate that human brain models secrete an endogenous hyaluronan matrix through expression of hyaluronan synthase. Hyaluronan is present at the synaptic cleft of nascent developing synapses. Through both genetic and pharmacological regulation of hyaluronan levels, we demonstrate that hyaluronan antagonizes excitatory synapse formation, preventing the emergence the hyperexcitability in developing neural networks. Furthermore, excitatory synapses contain the HA-receptor, CD44. In other tissue systems, the interaction between HA and CD44 activates RhoA signaling leading to actomyosin contractility. In our research, we demonstrate that similar to HA, RhoA signaling through its effector kinase, ROCK, also antagonizes excitatory synapse formation in developing neural networks. Together, our data supports a model in which synaptic HA suppresses excitatory synaptogenesis through interaction with CD44 and activation of RhoA/ROCK, resulting in the destabilization of synaptic contacts. We propose that HA-mediated regulation of synapse formation, critically regulates neural network development, and prevents the emergence of hyperexcitability in neural networks, which is characteristic of neurodevelopmental disorders.