Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior
Summary: Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723013967 |
| _version_ | 1797448072361410560 |
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| author | Jeffrey M. Malgady Alexander Baez Zachary B. Hobel Kimberly Jimenez Jack Goldfried Eric M. Prager Jennifer A. Wilking Qiangge Zhang Guoping Feng Joshua L. Plotkin |
| author_facet | Jeffrey M. Malgady Alexander Baez Zachary B. Hobel Kimberly Jimenez Jack Goldfried Eric M. Prager Jennifer A. Wilking Qiangge Zhang Guoping Feng Joshua L. Plotkin |
| author_sort | Jeffrey M. Malgady |
| collection | DOAJ |
| description | Summary: Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped. |
| first_indexed | 2024-03-09T14:05:05Z |
| format | Article |
| id | doaj.art-b0b11650ae514587bd0d6ac0e3f98936 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:05:05Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-b0b11650ae514587bd0d6ac0e3f989362023-11-30T05:07:00ZengElsevierCell Reports2211-12472023-11-014211113384Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behaviorJeffrey M. Malgady0Alexander Baez1Zachary B. Hobel2Kimberly Jimenez3Jack Goldfried4Eric M. Prager5Jennifer A. Wilking6Qiangge Zhang7Guoping Feng8Joshua L. Plotkin9Department of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA; Graduate Program in Neuroscience, College of Arts & Sciences, Stony Brook University, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA; Medical Scientist Training Program, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA; Graduate Program in Neuroscience, College of Arts & Sciences, Stony Brook University, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USAYang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USAYang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USADepartment of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA; Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY 11794, USA; Corresponding authorSummary: Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.http://www.sciencedirect.com/science/article/pii/S2211124723013967CP: NeuroscienceCP: Cell biology |
| spellingShingle | Jeffrey M. Malgady Alexander Baez Zachary B. Hobel Kimberly Jimenez Jack Goldfried Eric M. Prager Jennifer A. Wilking Qiangge Zhang Guoping Feng Joshua L. Plotkin Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior Cell Reports CP: Neuroscience CP: Cell biology |
| title | Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior |
| title_full | Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior |
| title_fullStr | Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior |
| title_full_unstemmed | Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior |
| title_short | Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior |
| title_sort | pathway specific alterations in striatal excitability and cholinergic modulation in a sapap3 mouse model of compulsive motor behavior |
| topic | CP: Neuroscience CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723013967 |
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