Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Abstract

Astrocytes are highly complex glial cells with numerous fine cellular processes which infiltrate the neuropil to interact with synapses. The mechanisms controlling the establishment of astrocytes’ remarkable morphology and how impairing astrocytic infiltration of the neuropil alters synaptic connectivity are largely unknown. Here we find that cortical astrocyte morphogenesis depends on direct contact with neuronal processes and occurs in tune with the growth and activity of synaptic circuits. Neuroligin (NL) family cell adhesion proteins, NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, cortical excitatory synapse formation and function is diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a novel mechanism of action for NLs and link astrocyte morphogenesis to synaptogenesis. Because NL mutations are implicated in various neurological disorders, these findings also offer an astrocyte-based mechanism of neural pathology.

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

“…The time window of astrocyte maturation overlaps with the period of synapse formation. Astrocytes secrete important protein signals that induce synapse formation (Allen et al, ; Blanco‐Suarez, Liu, Kopelevich, & Allen, ; Christopherson et al, ; Eroglu et al, ; Farhy‐Tselnicker et al, ; Kucukdereli et al, ; Pfrieger & Barres, ; Stogsdill et al, ; Ullian et al, ). To test whether HBEGF, EGFR, and P53 affect astrocytic interaction with synapses, we examined the expression of genes synapse‐inducing proteins.…”

Preventing neurodegeneration by adrenergic astroglial excitation

“…These functions were recently reviewed [51], and include regulation of synaptic formation, control of connectivity of synapses, integration and synchronization of neuronal networks and the maintenance of BBB integrity [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]. These functions were recently reviewed [51], and include regulation of synaptic formation, control of connectivity of synapses, integration and synchronization of neuronal networks and the maintenance of BBB integrity [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70].…”

Modern approaches to investigating non‐neuronal aspects of Alzheimer's disease

“…cellular heterogeneity alter function of these cells in a physiologic setting, and how might mutations in diseaserisk genes further alter cellular function leading to AD pathology? Equally, how do mutations in these genes alter normal astrocyte functions, such as the provision of neuronal support (34), synaptogenesis (35)(36)(37)(38)(39), synapse pruning (40,41), among others, which may account for altered neuronal function and consequent cognitive decline associated with AD? Answers to these questions will provide new insights into AD, and experiments to fully understand this are already underway in multiple laboratories around the world.…”

“…These barriers can become increasingly permeable to larger serum proteins following trauma, and in some diseases (57)(58)(59) [for review, see also (60,61)], the use of serum in CNS cell cultures changes their baseline morphology and transcriptome (16,42,(62)(63)(64). These cultures have been incredibly valuable for investigations of glial cell function (35)(36)(37)(38)52); however, with already highly expressed, disease-reactive transcripts in "baseline" cultures (15,16,18), it is likely that many false-negative results are achieved, as the baseline expression of many known reactive transcripts is so high (Fig. 2) that the d in expression changes following hypothesized "disease state-inducing molecules" may be too low to distinguish.…”