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Published on: February 26, 2018
Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity
Meng Chen1, Yehong Wan, Kristen Ade
1Center for Translational Neuroscience, Department of Medicine/Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Summary
SAPAP3 protein regulates endocannabinoid signaling in the brain. Its absence in mice causes abnormal synaptic plasticity by altering metabotropic glutamate receptor 5 (mGluR5) activity.
Area of Science:
- Neuroscience
- Synaptic Plasticity
- Molecular Mechanisms
Background:
- Endocannabinoid (eCB)-mediated retrograde signaling inhibits synaptic strength in the brain.
- The molecular basis for variability in eCB signaling across brain circuits is not well understood.
- SAP90/PSD-95-associated proteins (SAPAPs) are postsynaptic proteins found at excitatory synapses.
Purpose of the Study:
- To investigate the role of SAPAP3 in regulating eCB-mediated synaptic plasticity.
- To determine the molecular mechanisms underlying variations in eCB signaling thresholds.
Main Methods:
- Utilized Sapap3 knock-out (KO) mice and wild-type (WT) littermates.
- Examined excitatory synapses on striatal medium spiny neurons (MSNs).
- Assessed synaptic plasticity using electrophysiological techniques and pharmacological manipulations of mGluR5.
Main Results:
- Sapap3 KO MSNs exhibited anomalous eCB-mediated synaptic depression under non-standard conditions.
- This plasticity required dysregulated type 5 metabotropic glutamate receptors (mGluR5s), with increased surface expression and activity in KO MSNs.
- Pharmacological enhancement of mGluR5 in WT MSNs mimicked the KO phenotype, while further enhancement in KO MSNs had no additional effect.
Conclusions:
- SAPAP3 plays a crucial role in regulating postsynaptic mGluR5 activity.
- SAPAP3 acts as a molecular gatekeeper for inducing eCB-mediated synaptic plasticity.
- Altered SAPAP3 levels can shift the threshold for synaptic plasticity by modulating mGluR5 function.
