Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder
Open accessAbstract
Background Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) is an excitatory postsynaptic protein implicated in the pathogenesis of obsessive-compulsive behaviors. In mice, genetic deletion of Sapap3 causes obsessive-compulsive disorder (OCD)-like behaviors that are rescued by striatal expression of Sapap3, demonstrating the importance of striatal neurotransmission for the OCD-like behaviors. In the striatum, there are two main excitatory synaptic circuits, corticostriatal and thalamostriatal. Neurotransmission defects in either or both of these circuits could potentially contribute to the OCD-like behaviors of Sapap3 knockout (KO) mice. Previously, we reported that Sapap3 deletion reduces corticostriatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor-mediated synaptic transmission.Methods Whole-cell electrophysiological recording techniques in acute brain slices were used to measure synaptic transmission in the corticostriatal and thalamostriatal circuits of Sapap3 KO mice and littermate control animals. Transgenic fluorescent reporters identified striatopallidal and striatonigral projection neurons. SAPAP isoforms at corticostriatal and thalamostriatal synapses were detected using immunostaining techniques.Results In contrast to corticostriatal synapses, thalamostriatal synaptic activity is unaffected by Sapap3 deletion. At the molecular level, we find that another SAPAP family member, SAPAP4, is present at thalamostriatal, but not corticostriatal, synapses. This finding provides a molecular rationale for the functional divergence we observe between thalamic and cortical striatal circuits in Sapap3 KO mice.Conclusions These findings define the circuit-level neurotransmission defects in a genetic mouse model for OCD-related behaviors, focusing attention on the corticostriatal circuit for mediating the behavioral abnormalities. Our results also provide the first evidence that SAPAP isoforms may be localized to synapses according to circuit-selective principles.
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Electrophysiologic abnormalities in SAPAP3 knockout mice are specifically localized to corticostriatal, not thalamostriatal, synapses.
“Further characterization of these mice has demonstrated that electrophysiologic abnormalities are specifically localized to corticostriatal, and not thalamostriatal, synapses 92.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [92]
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 [21]
There are inputs (i.e., thalamic) that seem unaffected by the KO of Sapap3.
“Furthermore, for a thorough understanding of the pathologies in the Sapap3-KO mice, refinement of circuit specificity of synaptic dysfunction is necessary, as there are inputs (i.e., thalamic) that seem unaffected by the KO of Sapap3 [21].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [21]
SAPAP3−/− mice exhibit dysregulation of projections from cortex to striatum.
“For example, both OCD patients11, 12, 13, 14 and SAPAP3−/− 7, 8 exhibit dysregulation of projections from cortex to striatum.”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [8]
SAPAP3−/− display altered OFC-striatal activity and deficits in behavioral response inhibition that can be rescued by optogenetic stimulation of the OFC-striatal network.
“SAPAP3−/− display altered OFC‐striatal activity7, 8 and deficits in behavioral response inhibition that can be rescued by optogenetic stimulation of the OFC‐striatal network.16”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [8]
A compromised PFC-striatal network present in SAPAP3−/− is possibly responsible for the lack of adaptation to changing situational requirements.
“Thus, a compromised PFC‐striatal network present in SAPAP3−/−, which was shown to be involved in their excessive grooming,7, 8, 15, 16 is possibly responsible for the lack of adaptation to changing situational requirements.”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [8]
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- Authors
- Wan, Y., Ade, K. K., Caffall, Z., Ilcim Ozlu, M., Eroglu, C., Feng, G., & Calakos, N.
- Affiliations
- McGovern Institute for Brain Research (US)
- Duke University (US)
- Corresponding author
- Calakos, Nicole
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 75
- Issue
- 8
- Pages
- 623-630
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3687030
- OpenAlex
- W2071933629
- Cited by
- 118
- References
- 38
- Citations by year
- 2026: 10 · 2025: 5 · 2024: 15 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 3 · 2015: 11 · 2014: 5 · 2013: 3
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- National Institute of Mental Health (MH081201, R01MH081201, R01MH097104)
- National Institute on Drug Abuse (DA031833, R01DA031833)
- National Institute of Neurological Disorders and Stroke (R01NS064577, NS054840, T32NS051156, NS064577, K02NS054840)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- obsessive-compulsive disorder, corticostriatal circuits, AMPA receptors, striatopallidal neurons, striatonigral neurons, genetic mouse models
- MeSH terms
- Animals, Cerebral Cortex, Corpus Striatum, Disease Models, Animal, Mice, Transgenic, Nerve Tissue Proteins, Neural Pathways, Neurons, Obsessive-Compulsive Disorder, Synapses, Thalamus, Receptors, AMPA, Mice, Knockout, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Vesicular Glutamate Transport Protein 1, Vesicular Glutamate Transport Protein 2, Mice, In Vitro Techniques
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