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A presynaptic phosphosignaling hub for lasting homeostatic plasticity
Johannes Alexander Müller1, Julia Betzin2, Jorge Santos-Tejedor2
1Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, Germany; Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
Cell Reports
|April 20, 2022
Summary
Synaptic plasticity relies on protein phosphorylation. Serine arginine protein kinase 2 (SRPK2) and RIM1 protein regulate synaptic strength, maintaining neuronal network balance and preventing cognitive disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Stable neuronal network function depends on synaptic plasticity, where synapses adjust their strength based on neuronal activity levels.
- Dysregulation of synaptic plasticity is linked to cognitive disorders, highlighting the need to understand its underlying mechanisms.
- The precise molecular mechanisms governing homeostatic regulation in mammalian synapses are not fully understood.
Purpose of the Study:
- To investigate the role of the active zone (AZ) protein RIM1 phosphorylation in regulating synaptic glutamate release.
- To identify the specific protein kinase responsible for phosphorylating key sites on RIM1 involved in homeostatic plasticity.
- To elucidate the functional consequences of RIM1 phosphorylation by SRPK2 on synaptic structure and function.
Main Methods:
- Utilized biochemical assays to assess the phosphorylation status of RIM1 at various positions.
- Employed genetic manipulation to study the necessity and sufficiency of RIM1 phosphorylation at position S1045 for homeostatic plasticity.
- Investigated the impact of serine arginine protein kinase 2 (SRPK2) on synaptic release and RIM1 localization using imaging techniques.
Main Results:
- The phosphorylation status of specific sites on RIM1 is critical for synaptic glutamate release.
- Phosphorylation at position RIM1-S1045 is both necessary and sufficient for silencing-induced homeostatic plasticity.
- Serine arginine protein kinase 2 (SRPK2) maintains RIM1 phosphorylation at S1045, driving synaptic release upscaling.
- SRPK2-mediated upscaling results in increased RIM1 nanoclusters and docked vesicles at the AZ.
- This effect is dependent on RIM1 presence and is blocked by a non-phosphorylatable RIM1 mutant (RIMS1045E).
Conclusions:
- SRPK2 and RIM1 form a presynaptic phosphosignaling hub crucial for regulating synaptic strength.
- This signaling pathway plays a vital role in maintaining the homeostatic balance of neuronal network coupling.
- Understanding this mechanism offers insights into preventing cognitive disorders linked to synaptic dysfunction.
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