Necl2/3-mediated mechanism for tripartite synapse formation.
Osamu Nozawa1, Muneaki Miyata1, Hajime Shiotani1
1Division of Pathogenetic Signaling, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0047, Japan.
Development (Cambridge, England)
|December 2, 2022
Summary
Researchers uncovered how astrocytes and neurons form tripartite synapses. Astrocytic Necl2 and axonal Necl3, along with glutamate, are key to forming these crucial brain connections.
Area of Science:
- Neuroscience
- Cell Biology
- Synaptic Plasticity
Background:
- Astrocytes interact with synapses, forming tripartite synapses that regulate neuronal function.
- The molecular mechanisms underlying tripartite synapse formation are not fully understood.
- Perisynaptic astrocyte processes (PAPs) are critical for astrocyte-synapse communication.
Purpose of the Study:
- To elucidate the molecular mechanisms of tripartite glutamatergic synapse formation.
- To investigate the roles of astrocytic Necl2 and axonal Necl3 in astrocyte-synapse interactions.
- To understand astrocyte functional polarization in synapse formation.
Main Methods:
- Developed an in vitro co-culture system of mouse astrocytes and neurons.
- Utilized neuronal activity-dependent induction of astrocyte ramifications and PAP formation.
- Investigated Necl2/3 trans-interactions and their effects on glutamate transporters and ion channels.
- Confirmed findings in vivo using Necl3 and Necl2/3 knockout mouse models.
Main Results:
- Neuronal activity was required for astrocyte ramifications, involving glutamate and astrocytic mGluR5.
- Astrocytic Necl2 trans-interacted with axonal Necl3, promoting astrocyte-synapse interaction and polarization.
- Necl2/3 interaction recruited EAAT1/2 and Kir4.1 to PAPs, increasing functional synapse number.
- These mechanisms were validated in vivo in knockout mouse models.
Conclusions:
- Astrocytic Necl2, synaptically released glutamate, and axonal Necl3 cooperatively form tripartite glutamatergic synapses.
- Necl2/3 trans-interaction is essential for astrocyte functional polarization and synapse maturation.
- This study reveals novel molecular mechanisms for astrocyte-synapse interactions in vitro and in vivo.
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