Molecular Mechanisms of Synaptic Assembly by Cortical Astrocytes

The brain, the source of human cognition, is composed of numerous cell types and a staggering number (over 1 quadrillion) of specialized connections called synapses. Each central nervous system (CNS) synapse is a complex entity organized as a presynaptic axon terminal and a postsynaptic dendritic structure, which pass chemical signals from one neuron to the next. How does each synapse form and how do synapses assemble into organized networks that permit cognition?

Research from the past two decades have identified that glial cells, predominantly astrocytes, regulate the formation and function of CNS synapses. Astrocytes are morphologically complex cells that interact with and ensheathe synapses through fine perisynaptic astrocyte processes. However, the molecular mechanisms of astrocyte development lay largely unknown. Furthermore, it is unclear how the morphology of the astrocyte is linked to its function as a regulator of synapse formation and function. Notwithstanding, more than a dozen astrocyte-secreted factors have been discovered that govern synaptogenesis, including proteins such as thrombospondins, glypicans, and hevin.

Here, I examine the molecular mechanism of astrocyte-synapse interactions and how excitatory synapses are assembled in the CNS using the mouse as a model system. First, I investigated the mechanism of hevin-induced thalamocortical excitatory synapse formation. I find that hevin trans-synaptically binds to two neuronal cell adhesion molecules, neurexin-1 and neuroligin-1B and that this molecular bridge is critical for the formation and plasticity of thalamocortical synapses in the cerebral cortex. Second, I uncover that astrocytes express a family of cell adhesion molecules, the neuroligins, which are critical for governing the developmental morphogenesis of astrocytes. Furthermore, I discover that astrocytic neuroligins are essential to establish the proper balance between synaptic excitation and inhibition in the brain.

Taken together, the data presented here detail two mechanisms of how astrocytes control the assembly of CNS synapses. Moreover, they highlight how bidirectional signals between astrocytes and neurons properly form the brain and its specialized connections. The research performed herein is of high importance to the clinical neuroscience community, because the genes investigated (neuroligins, neurexins, and hevin) are linked to neurological disorders such as autism and schizophrenia. By understanding of how these cells communicate in development and disease, the neuroscience field will hopefully be able to design therapeutics aimed at restoring cognition for patients afflicted with neurological impairments.