Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior
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
Affiliations
Jeffrey M. Malgady
Department 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, USA
Alexander Baez
Department 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, USA
Zachary B. Hobel
Department 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, USA
Kimberly Jimenez
Department of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA
Jack Goldfried
Department of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA
Eric M. Prager
Department of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA
Jennifer A. Wilking
Department of Neurobiology & Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA
Qiangge Zhang
Yang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Guoping Feng
Yang 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, USA
Joshua L. Plotkin
Department 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 author
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.
