HepaCAM controls astrocyte self-organization and coupling.

Astrocytes extensively infiltrate the neuropil to regulate critical aspects of synaptic development and function. This process is regulated by transcellular interactions between astrocytes and neurons via cell adhesion molecules. How astrocytes coordinate developmental processes among one another to parse out the synaptic neuropil and form non-overlapping territories is unknown. Here we identify a molecular mechanism regulating astrocyte-astrocyte interactions during development to coordinate astrocyte morphogenesis and gap junction coupling. We show that hepaCAM, a disease-linked, astrocyte-enriched cell adhesion molecule, regulates astrocyte competition for territory and morphological complexity in the developing mouse cortex. Furthermore, conditional deletion of Hepacam from developing astrocytes significantly impairs gap junction coupling between astrocytes and disrupts the balance between synaptic excitation and inhibition. Mutations in HEPACAM cause megalencephalic leukoencephalopathy with subcortical cysts in humans. Therefore, our findings suggest that disruption of astrocyte self-organization mechanisms could be an underlying cause of neural pathology.

Cell adhesion molecules regulating astrocyte-neuron interactions.

A tripartite synapse comprises a neuronal presynaptic axon and a postsynaptic dendrite, which are closely ensheathed by a perisynaptic astrocyte process. Through their structural and functional association with thousands of neuronal synapses, astrocytes regulate synapse formation and function. Recent work revealed a diverse range of cell adhesion-based mechanisms that mediate astrocyte-synapse interactions at tripartite synapses. Here, we will review some of these findings unveiling a highly dynamic bidirectional signaling between astrocytes and synapses, which orchestrates astrocyte morphological maturation and synapse development. Moreover, we will discuss the roles of these newly discovered molecular pathways in brain physiology and function both in health and disease.

Role of astrocytes in synapse formation and maturation.

Astrocytes are the most abundant glial cells in the mammalian brain and directly participate in the proper functioning of the nervous system by regulating ion homeostasis, controlling glutamate reuptake, and maintaining the blood-brain barrier. In the last two decades, a growing body of work also identified critical roles for astrocytes in regulating synaptic connectivity. Stemming from the observation that functional and morphological development of astrocytes occur concurrently with synapse formation and maturation, these studies revealed that both developmental processes are directly linked. In fact, astrocytes both physically contact numerous synaptic structures and actively instruct many aspects of synaptic development and function via a plethora of secreted and adhesion-based molecular signals. The complex astrocyte-to-neuron signaling modalities control different stages of synaptic development such as regulating the initial formation of structural synapses as well as their functional maturation. Furthermore, the synapse-modulating functions of astrocytes are evolutionarily conserved and contribute to the development and plasticity of diverse classes of synapses and circuits throughout the central nervous system. Importantly, because impaired synapse formation and function is a hallmark of many neurodevelopmental disorders, deficits in astrocytes are likely to be major contributors to disease pathogenesis. In this chapter, we review our current understanding of the cellular and molecular mechanisms by which astrocytes contribute to synapse development and discuss the bidirectional secretion-based and contact-mediated mechanisms responsible for these essential developmental processes.