Sapap3 Deletion Anomalously Activates Short-Term Endocannabinoid-Mediated Synaptic Plasticity
Open accessAbstract
Retrograde synaptic signaling by endocannabinoids (eCBs) is a widespread mechanism for activity-dependent inhibition of synaptic strength in the brain. Although prevalent, the conditions for eliciting eCB-mediated synaptic depression vary among brain circuits. As yet, relatively little is known about the molecular mechanisms underlying this variation, although the initial signaling events are likely dictated by postsynaptic proteins. SAP90/PSD-95-associated proteins (SAPAPs) are a family of postsynaptic proteins unique to excitatory synapses. Using Sapap3 knock-out (KO) mice, we find that, in the absence of SAPAP3, striatal medium spiny neuron (MSN) excitatory synapses exhibit eCB-mediated synaptic depression under conditions that do not normally activate this process. The anomalous synaptic plasticity requires type 5 metabotropic glutamate receptors (mGluR5s), which we find are dysregulated in Sapap3 KO MSNs. Both surface expression and activity of mGluR5s are increased in Sapap3 KO MSNs, suggesting that enhanced mGluR5 activity may drive the anomalous synaptic plasticity. In direct support of this possibility, we find that, in wild-type (WT) MSNs, pharmacological enhancement of mGluR5 by a positive allosteric modulator is sufficient to reproduce the increased synaptic depression seen in Sapap3 KO MSNs. The same pharmacologic treatment, however, fails to elicit further depression in KO MSNs. Under conditions that are sufficient to engage eCB-mediated synaptic depression in WT MSNs, Sapap3 deletion does not alter the magnitude of the response. These results identify a role for SAPAP3 in the regulation of postsynaptic mGluRs and eCB-mediated synaptic plasticity. SAPAPs, through their effect on mGluR activity, may serve as regulatory molecules gating the threshold for inducing eCB-mediated synaptic plasticity.
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Corticostriatal synaptic deficits in Sapap3-KO mice have been assessed in mice aged 3-8 weeks.
“In contrast, corticostriatal synaptic deficits have been assessed in mice aged 3-8 weeks [19][20][21][22][23].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [19]
Constitutive KO of Sapap3 causes synaptic deficits already in preadolescence.
“However, since constitutive KO of Sapap3 causes synaptic deficits already in preadolescence [9,[19][20][21], we hypothesized that excessive grooming behavior must manifest early in life, which we confirmed here.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [19]
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- Authors
- Chen, M., Wan, Y., Ade, K., Ting, J., Feng, G., & Calakos, N.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- McGovern Institute for Brain Research (US)
- Corresponding author
- Calakos, N.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-06-29
- Volume
- 31
- Issue
- 26
- Pages
- 9563-9573
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3367431
- OpenAlex
- W2081491493
- Cited by
- 82
- References
- 72
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 4 · 2012: 5
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (MH081201, F32MH084460, R01MH081201)
- National Institute of Neurological Disorders and Stroke (R01NS064577, NS054840, T32NS051156, NS064577, K02NS054840)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- endocannabinoids, synaptic depression, synaptic plasticity, mGluR5, metabotropic glutamate receptors, striatal medium spiny neurons, postsynaptic proteins, positive allosteric modulators, excitatory synapses, short-term plasticity
- MeSH terms
- Analysis of Variance, Animals, Corpus Striatum, Electrophysiology, Nerve Tissue Proteins, Synaptic Transmission, Neuronal Plasticity, Neurons, Synapses, Receptors, Metabotropic Glutamate, Mice, Knockout, Mice, Cannabinoid Receptor Modulators, Endocannabinoids
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