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.

SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had corticostriatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.

The recently cloned rat vanilloid receptor, VR1, can be activated by capsaicin, acid, and heat. To determine the molecular mechanisms facilitating channel opening in response to these stimuli, VR1 and six channels containing charge neutralization point mutations surrounding the putative channel pore domain were expressed and characterized in Xenopus laevis oocytes. Steady-state doseresponse relationships, current-voltage relationships, ionic selectivities, and single-channel properties were recorded using voltage-clamp techniques. Three of the mutant channels are significantly more sensitive to capsaicin than is wild-type VR1, whereas none differed in their activation by acidic pH or temperature. Furthermore, one of the mutants has lost all positive cooperativity for capsaicin activation (Hill coefficient Х 1, VR1 Х 2), is much more selective for Ca 2؉ , and exhibits a lower efficacy for acid than for capsaicin activation. Single-channel recordings show that capsaicin-and acid-activated channels have the same conductance, that the three mutants with increased capsaicin sensitivity exhibit higher open probabilities at submaximal capsaicin concentrations, and that the gating properties of capsaicin activation differ from those of acid activation. These data indicate that VR1 undergoes conformational changes upon capsaicin binding that it does not undergo in response to activation by protons or thermal stimuli. Furthermore, these structural rearrangements include the putative pore domain and reveal the location of an intracellular domain that contributes to the positive cooperativity seen for capsaicin activation.C apsaicin, the primary pungent compound in ''hot'' chili peppers, produces pain and inflammation when placed on skin or mucus membranes. These responses are a consequence of capsaicin activating nonselective cation channel receptors within C and A␦ nociceptors and inducing the release of peptides and other transmitters from their peripheral and central terminals (1). Although a number of reports have demonstrated the existence of capsaicin receptors in sensory neurons (2, 3), the cloning of rat vanilloid receptor 1 (VR1) (4) was a breakthrough in understanding their properties and physiological functions (3, 5). VR1 subunits have now been identified in peripheral and central terminals of neurons in sensory ganglia (1,3,4,6,7). Electrophysiological studies of expressed VR1 receptors show that they are activated independently by capsaicin (EC 50 ϭ 0.7 M), acid (pH 50 ϭ 5.4), and elevated temperatures Ն 43°C (3, 6). These conditions are similar to those found in some physiological states (2,3,8). Further findings were that two or more of these activation pathways can act in concert to increase the sensitivity of VR1 receptors to any one stimulus (6,8). To determine protein domains important for the activation of VR1 by capsaicin, protons, and heat, we constructed a number of VR1 point mutants and measured their responsiveness to these three activators. We found that mutations near the pore of VR1 channels ca...