Sapap3 Deletion Causes mGluR5-Dependent Silencing of AMPAR Synapses
Open accessAbstract
Synaptic transmission mediated by AMPA-type glutamate receptors (AMPARs) is regulated by scaffold proteins in the postsynaptic density. SAP90/PSD-95-associated protein 3 (SAPAP3) is a scaffold protein that is highly expressed in striatal excitatory synapses. While loss of SAPAP3 is known to cause obsessive-compulsive disorder-like behaviors in mice and reduce extracellular field potentials in the striatum, the mechanism by which SAPAP3 regulates excitatory neurotransmission is largely unknown. This study demonstrates that Sapap3 deletion reduces AMPAR-mediated synaptic transmission in striatal medium spiny neurons (MSNs) through postsynaptic endocytosis of AMPARs. Striatal MSNs in Sapap3 KO mice have fewer synapses with AMPAR activity and a higher proportion of silent synapses. We further find that increased metabotropic glutamate receptor 5 (mGluR5) activity in Sapap3 KO mice underlies the decrease in AMPAR synaptic transmission and excessive synapse silencing. These findings suggest a model whereby the normal role of SAPAP3 is to inhibit mGluR5-driven endocytosis of AMPARs. The results of this study provide the first evidence for the mechanism by which the SAPAP family of scaffold proteins regulates AMPAR synaptic activity.
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Synaptic deficits in Sapap3-KO mice persist in adulthood.
“Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [20]
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 [20]
PPR did not differ between genotypes.
“Pairedpulse ratios (PPR), a measure for presynaptic release probability, did not differ between genotypes (Fig. 2f), which is consistent with findings from 3 weeks old mice [20].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [20]
Synaptic deficits of 3 weeks old mice persist to adulthood.
“This showed that synaptic deficits of 3 weeks old mice [20] persist to adulthood.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [20]
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 [20]
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References 24 · Cited by 101
- Authors
- Wan, Y., Feng, G., & Calakos, N.
- Affiliations
- Duke University (US)
- Corresponding author
- Calakos, Nicole
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-11-16
- Volume
- 31
- Issue
- 46
- Pages
- 16685-16691
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3475185
- OpenAlex
- W2057912349
- Cited by
- 101
- References
- 24
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 10 · 2023: 4 · 2022: 6 · 2021: 2 · 2020: 9 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 10 · 2015: 9 · 2014: 9 · 2013: 7 · 2012: 3
- FWCI
- 2.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hartwell Foundation
- National Alliance for Research on Schizophrenia and Depression
- Simons Foundation Autism Research Initiative
- National Institute of Mental Health (MH081201, R01MH081201)
- National Institute of Neurological Disorders and Stroke (R01NS064577, NS054840, NS064577-S1, NS064577, K02NS054840)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- mGluR5, AMPA receptor endocytosis, silent synapses, striatal medium spiny neurons, postsynaptic scaffolds, synaptic transmission, obsessive-compulsive disorder, postsynaptic density
- MeSH terms
- Animals, Animals, Newborn, Biophysics, Electric Stimulation, Endocytosis, Mice, Transgenic, Nerve Tissue Proteins, Synaptic Transmission, Piperidines, Pyrazoles, Synapses, Receptors, Dopamine D1, Receptors, Dopamine D2, Receptors, AMPA, Receptors, Metabotropic Glutamate, Patch-Clamp Techniques, Excitatory Amino Acid Agents, Statistics, Nonparametric, Excitatory Postsynaptic Potentials, Green Fluorescent Proteins, Mice, Receptor, Metabotropic Glutamate 5, In Vitro Techniques
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