Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Abstract

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striatothalamo-cortical circuitry is implicated in OCD, though the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of SAPAP3 exhibit increased anxiety and compulsive grooming behavior leading to facial hair loss and skin lesions; both behaviors are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural, and biochemical studies of SAPAP3 mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of SAPAP3 in the striatum rescues the synaptic and behavioral defects of SAPAP3 mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviors.

Perinatal western‐type diet and associated gestational weight gain alter postpartum maternal mood

“…Given the finding of increased anxiety‐like behavior in postpartum HFD dams, it is possible that this excessive self‐grooming represents a repetitive, anxious phenotype (Shmelkov et al., 2010; Welch et al., 2007). …”

“…It is also possible that HFD may be protective against depressive‐like behavior, although future studies are needed to confirm this hypothesis. Excessive self‐grooming, observed in HFD dams, is one of the hallmark symptoms in an OCD mouse model, which is also associated with increased anxiety‐like behaviors (Shmelkov et al., 2010; Welch et al., 2007). Notably, studies in humans have found that up to one third of women report obsessive‐compulsive behaviors in the early postpartum period, often in association with negative maternal mood (Miller, Hoxha, Wisner, & Gossett, 2015).…”

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

“…Pathological grooming behavior has been hypothesized to be related to obsessive-compulsive disorder (OCD)-in humans and other animals-in terms of phenomenology and possible selective response to serotonergic drugs Rapoport et al, 1992;Bordnick et al, 1994;Overall and Dunham, 2002;Graf et al, 2003; but also see Bloch et al, 2007], and this behavior in Sapap3 mutant mice led Welch et al to perform a set of experiments testing the extent to which these mouse behaviors resemble OCD in humans. The Sapap3 mutant mice showed increased anxiety-like behavior in open field, dark-to-light emergence, and elevated zero maze tests, and 6-day fluoxetine treatment of these mice reduced both excessive grooming and anxiety-like behaviors [Welch et al, 2007]. Cortico-striatal circuits appear dysfunctional in persons with OCD [Graybiel and Rauch, 2000;Saxena and Rauch, 2000;Aouizerate et al, 2004;Swedo and Snider, 2004;Menzies et al, 2007]; thus, it is highly relevant that Sapap3 mutant mice also showed defects in cortico-striatal synapses in electrophysiological, biochemical, and structural studies.…”

“…There are four highly homologous members of the SAPAP family, and a recent study found that mice with a deletion of the Sapap3 gene groom themselves excessively [Welch et al, 2007]. This grooming behavior appears similar in nature to that of wild-type mice but is much more frequent, leading to facial hair and skin removal in the absence of peripheral cutaneous defects [Welch et al, 2007].…”

“…There are four highly homologous members of the SAPAP family, and a recent study found that mice with a deletion of the Sapap3 gene groom themselves excessively [Welch et al, 2007]. This grooming behavior appears similar in nature to that of wild-type mice but is much more frequent, leading to facial hair and skin removal in the absence of peripheral cutaneous defects [Welch et al, 2007]. Pathological grooming behavior has been hypothesized to be related to obsessive-compulsive disorder (OCD)-in humans and other animals-in terms of phenomenology and possible selective response to serotonergic drugs Rapoport et al, 1992;Bordnick et al, 1994;Overall and Dunham, 2002;Graf et al, 2003; but also see Bloch et al, 2007], and this behavior in Sapap3 mutant mice led Welch et al to perform a set of experiments testing the extent to which these mouse behaviors resemble OCD in humans.…”