Control of neural development and function by glial neuroligins

Abstract

Neuroligins are a family of cell adhesion molecules, which are best known for their functions as postsynaptic components of the trans-synaptic neurexin-neuroligin complexes. Neuroligins are highly conserved across evolution with important roles in the formation, maturation and function of synaptic structures. Mutations in the genes that encode for neuroligins have been linked to a number of neurodevelopmental disorders such as autism and schizophrenia, which stem from synaptic pathologies. Owing to their essential functions in regulating synaptic connectivity and their link to synaptic dysfunction in disease, previous studies on neuroligins have focused on neurons. Yet a recent work reveals that neuroligins are also expressed in the central nervous system by glial cells, such as astrocytes and oligodendrocytes, and perform important roles in controlling synaptic connectivity in a non-cell autonomous manner. In this review, we will highlight these recent findings demonstrating the important roles of glial neuroligins in regulating the development and connectivity of healthy and diseased brains.

Figure 1:. Astrocytic NL2 controls astrocyte morphogenesis.

A) Schematic of neuroligin- neurexin interactions at the synapse. Pre-synaptic α- and β-neurexins interact with postsynaptic neuroligins to recruit receptors to the post-synaptic density and calcium channels and synaptic vesicles to the active zone. B) Electron micrograph depicting an astrocyte (cyan) contacting both a dendrite (red) and an axon (green) at the synapse. C) 3D reconstruction of B. D) Schematic of postnatal mouse astrocyte development. From P7 to P21 astrocyte territories rapidly increase in size and infiltrate the neuropil, coincident with synaptogenesis. With loss of astrocytic NL2 (cKO) astrocytes are smaller and less complex, with decreased ability to infiltrate the neuropil. E) Max projections of confocal z-stacks of medial prefrontal cortical astrocytes at P21. NL2^loxP/+ or ^loxP/loxP, both carrying a floxed Rosa-TdTomato allele, were postnatally injected with Cre plasmid to produce sparse CTRL or cKO astrocytes, respectively. Scale bar = 25μm. Images from 1B-C are courtesy of Dr. W. Chris Risher, Marshall University.

Figure 2:. Proposed models for astrocytic NL function at synapses.

A) Schematic demonstrating a cooperative model of astrocytic (blue) NLs interacting with neuronal (grey) NRXs (or vice versa, question mark). These transcellular interactions may stabilize synapses by restricting the diffusion of neuronal NRXs and NLs from the synaptic cleft. Conversely, in a competitive model (B), binding of astrocytic NLs to neuronal NRXs diminishes synaptic strength by replacing neuronal NLs.