Valence processing alterations in SAPAP3 knockout mice and human OCD

Kajs, Bridget L.; Roessel, Peter J. van; Davis, Gwynne L.; Williams, Leanne M.; Rodriguez, Carolyn I.; Gunaydin, Lisa A.

doi:10.1016/j.jpsychires.2022.05.024

Cited by 9 publications

(8 citation statements)

References 56 publications

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“…Following PMA acquisition and expression, KOs and WTs were trained on ERP to determine if KOs would have impaired extinction learning, consistent with phenotypes observed in fear conditioning paradigms (Kajs et al, 2022). In line with our predictions, KOs were slower to reengage in reward-seeking during tone periods, suggesting delayed extinction.…”

Section: Discussionmentioning

confidence: 97%

“…OCD patients are biased towards appraising negative emotional stimuli (Kajs et al, 2022), have faster acquisition from negative versus positive outcomes (Endrass et al, 2011), and show more intolerance and distress during uncertainty, even in situations with low uncertainty or known risk (Jacoby et al, 2023). We therefore wanted to examine avoidance learning in an OCD-relevant mouse model to begin to address mechanisms underlying threat- and risk-assessment.…”

Section: Discussionmentioning

confidence: 99%

“…Sapap3 knockout mice (KOs) are a common model for OCD-related behaviors, exhibiting compulsive grooming, elevated anxiety (Lamothe et al, 2023;van den Boom et al, 2019;Welch et al, 2007), and deficits in behavioral flexibility (Hadjas et al, 2019;Manning et al, 2019;van den Boom et al, 2019) which map onto symptoms observed in clinical populations (Benzina et al, 2021;Burguiere et al, 2015). Recent studies also demonstrate enhanced fear conditioning and impaired fear extinction in KOs [ (Kajs et al, 2022), LaPalombara et al, unpublished observations], suggesting heightened sensitivity to negative stimuli and threat appraisal. However, KO performance in active avoidance tasks has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

“…The link between obsessions, compulsions, and avoidance is further highlighted by studies showing that impairments in threat processing and avoidance are associated with compulsion severity and poorer treatment outcomes in OCD (McGuire et al, 2012; Wheaton et al, 2018; Wheaton et al, 2021). Additionally, OCD patients exhibit biases to attend to and learn to avoid negative stimuli (Endrass et al, 2011; Kajs et al, 2022), habitually avoid devalued threats (Gillan et al, 2014), have devaluation impairments on a rule-based avoidance task with longer illness duration (Chase et al, 2020), and inappropriately perform avoidant behaviors to safety cues (De Kleine et al, 2023). Together, these studies suggest that active avoidance is a persistent component that could contribute to the development and severity of OCD, but little is known about the mechanisms underlying its dysregulation.…”

Section: Introductionmentioning

confidence: 99%

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Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Manning,

Crummy,

LaPalombara

et al. 2024

Preprint

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Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive aversive thoughts (obsessions) and repetitive rituals aimed at avoiding these aversive outcomes (compulsions), which interferes with patients' engagement with other important aspects of their lives. This cycling relationship between obsessions and compulsions highlights a potential role of impaired threat processing and avoidance behavior in OCD symptoms. The most effective behavioral therapy for OCD, exposure with response prevention (ERP), aims to break this cycle. However, it can be difficult for patients to access and engage with, suggesting a need for improved understanding of the neural mechanisms of threat processing and avoidance behavior in OCD to guide development of new and more effective treatments. Platform mediated avoidance (PMA) has proven to be a useful translational paradigm for use in rodents to examine avoidance neurobiology and models relevant to OCD, such as ERP and overtraining-induced persistent avoidance. However, to date this protocol has only been used in rats, and studies in transgenic mouse models relevant to OCD may shed further light on neural mechanisms relevant to disturbances in avoidance and threat processing in the disorder. To address this gap, we tested Sapap3 knockout (KO) mice, a leading preclinical model in OCD research, in the PMA task. Using this paradigm, we examined avoidance acquisition, expression, and extinction, as well as reward seeking under motivational conflict in two separate cohorts conditioned using higher (0.4 mA) or lower (0.24 mA) intensity shock. Surprisingly, the most striking difference observed in Sapap3-KOs vs control mice was heightened suppression of lever pressing for rewards during a tone signaling impending threat, suggesting a shift in action selection under motivational conflict (genotype effect avoidance conditioning: 0.24 mA cohort p=0.011, 0.4 mA cohort p=0.07; avoidance extinction: 0.24 mA p=0.057, 0.4 mA p=0.042). Avoidance responding was also acquired more slowly in Sapap3-KOs trained with a low intensity shock (time x genotype interaction p=0.025) and was extinguished more robustly following ERP (genotype effect p=0.043). In contrast, avoidance was similar between Sapap3 KOs and WT littermate controls trained using higher intensity shock (0.4 mA cohort time effect p<0.0001). Expression of the immediate early gene c-Fos associated with reinstatement of avoidance after ERP showed preliminary evidence for decreased activity of medial orbitofrontal cortex (mOFC) in KOs which may contribute to observed differences in PMA performance (KO vs WT mOFC c-Fos t-test p=0.0456). Together these findings suggest that mOFC dysfunction may contribute to increases in the influence of threats vs rewards over action selection in an animal model with relevance to OCD, and that the Sapap3-KO model presents valuable opportunities for deeper mechanistic investigation of avoidance and threat processing relevant to the human disorder.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Manning,

Crummy,

LaPalombara

et al. 2024

Preprint

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“…Owing to the promising association between SAPAP3 and OCD, much more attention has been given to Sapap3 -mutant mice—a well-established OCD-relevant murine model displaying repetitive self-grooming behavior, augmented anxiety, cognitive inflexibility, imbalances between goal-directed and habitual behavior, selective deficits in behavioral response inhibition, insensitivity to reward devaluation, altered valence processing, hypolocomotion, disrupted sleep patterns, normal preference motivation for sucrose, and Pavlovian learning [ 13 , 102 , 104 , 106 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ]. Convergent evidence from structural, biochemical, electrophysiological, and neural circuitry studies of Sapap3 -mutant mice demonstrates and emphasizes the crucial role of SAPAP3 in corticostriatal synapses and striatum-based circuitry in OCD-like phenotypes.…”

Section: Mutational Studies In Murine Sapap Modelsmentioning

confidence: 99%

SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

Bai

Wang

2022

Cells

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Excitatory (glutamatergic) synaptic transmission underlies many aspects of brain activity and the genesis of normal human behavior. The postsynaptic scaffolding proteins SAP90/PSD-95-associated proteins (SAPAPs), which are abundant components of the postsynaptic density (PSD) at excitatory synapses, play critical roles in synaptic structure, formation, development, plasticity, and signaling. The convergence of human genetic data with recent in vitro and in vivo animal model data indicates that mutations in the genes encoding SAPAP1–4 are associated with neurological and psychiatric disorders, and that dysfunction of SAPAP scaffolding proteins may contribute to the pathogenesis of various neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, obsessive compulsive disorders, Alzheimer’s disease, and bipolar disorder. Here, we review recent major genetic, epigenetic, molecular, behavioral, electrophysiological, and circuitry studies that have advanced our knowledge by clarifying the roles of SAPAP proteins at the synapses, providing new insights into the mechanistic links to neurodevelopmental and neuropsychiatric disorders.

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Late development of OCD-like phenotypes in Dlgap1 knockout mice

Minagawa,

Hayakawa,

Akimoto

et al. 2024

Psychopharmacology

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Rationale Despite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible. Objective To examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine. Methods and results Newly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6–7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine. Conclusion Usefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested.

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Valence processing alterations in SAPAP3 knockout mice and human OCD

Cited by 9 publications

References 56 publications

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Sapap3knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

Late development of OCD-like phenotypes in Dlgap1 knockout mice

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