Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive. We developed an in vitro co-culture system for mouse astrocytes and neurons that induced astrocyte ramifications and PAP formation. Co-cultured neurons were required for astrocyte ramifications in a neuronal activity-dependent manner and synaptically released glutamate and activation of astrocytic mGluR5 metabotropic glutamate receptor were likely involved in astrocyte ramifications. Astrocytic Necl-2/CADM1 trans-interacted with axonal Necl-3/CADM2, inducing astrocyte-synapse interactions and astrocyte functional polarization by recruiting EAAT1/2 glutamate transporters and Kir4.1 K+ channel to the PAPs, without affecting astrocyte ramifications. This Necl-2/3 trans-interaction increased functional synapse number. Thus, astrocytic Necl-2, synaptically released glutamate, and axonal Necl-3 cooperatively formed tripartite glutamatergic synapses in vitro. Studies on hippocampal mossy fiber synapses in Necl-3 knockout and Necl-2/3 double knockout mice confirmed these novel mechanisms for astrocyte-synapse interactions and astrocyte functional polarization in vivo.
A novel Necl-2/3-mediated mechanism for tripartite synapse formation
These authors contributed equally to the work
Pathway to Independence programme
We’re excited to announce our new Pathway to Independence programme, aimed at supporting postdocs as they go on the job market. Find out more about the scheme in our Editorial.
Call for papers: Metabolic and Nutritional Control of Development and Regeneration
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Preprints in Development
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As part of our efforts to support the use of preprints and help curate the preprint literature, we are delighted to launch a new article type: ‘In preprints’. These pieces will discuss one or more recent preprints and place them in a broader context.
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