An Obsessive Compulsive Mouse

Obsessive-Compulsive Disorder (OCD) affects about 2% of the population. It is characterized by persistent intrusive thoughts (obsessions), repetitive actions (compulsions), and excessive anxiety. As anyone who know someone with PWS can appreciate, OCD behaviors are very common in the PWS population, with many individuals showing symptoms that interfere with daily living and/or result in moderate to high levels of symptom-related distress (Dykens, 1996; State and Dykens 2000).

OCD symptoms in PWS do not only relate to food and eating issues, as is commonly assumed. Frequently observed symptoms include compulsive hoarding, ordering and arranging, a need to say things, a concern with symmetry and exactness, and redoing things until they are “perfectâ€. The study of OCD has the potential to help the millions of people who suffer from this disorder worldwide, and may also add to our understanding of the etiology of PWS.

Welch and colleagues [Cortico-striatal synaptic defects and OCD-like behaviors in Sapap3-mutant mice, Nature 2007] have recently explored OCD-like behaviors in mice with alterations to the cortico-striato-thalamo-cortical circuitry, a loop in the brain known to play a role in OCD involving the cortex, the striatum, and the thalamus. These investigators deleted the gene encoding the SAPAP3 protein from mice. This protein is a scaffolding™ protein that normally sits at the neuronal membrane, on the receiving end of neuron-to-neuron transmissions (postsynaptic membrane). There, it is thought to regulate excitatory transmission by regulating which neurotransmitter receptors and signaling molecules are present at the synaptic junction (where the neurons meet). Of the family of SAPAP proteins, SAPAP3 is the only one expressed in the striatum - a region of the brain comprised of the caudate nucleus, the putamen, and nucleus accumbens, which is important in integrating signals from the cortex and developing a response (motor or cognitive).
Sapap3 knockout mice develop normally, but by 4-6 months of age, they develop severe lesions on their neck, head, and snout regions that are due to excessive and injurious self-grooming that is present throughout the day and disrupts normal sleep patterns. Excessive self-grooming is one of the features of OCD in humans and is reported very often in those with PWS, particularly in the form of skin picking of the face, arms, and legs.

Sapap3
mice also show features of excessive anxiety unrelated to OCD-like behaviors, including less time spent exploring open-field areas and taking more time to cross risky regions of a novel environment. Interestingly, fluoxetine, a drug that successfully treats OCD in humans by inhibiting the reuptake of serotonin, decreases self-injurious excessive grooming and anxiety in these mice.

Electrophysiology of the cortico-striatal system indicates reduced excitatory responses in the Sapap3 mice, and suggests the problem is most likely due to decreased glutamate responses post-synaptically. Finally, viral-mediated expression of SAPAP3 specifically in the striatum of early postnatal mice formerly lacking the protein was able to “rescue†the phenotype, decreasing excessive grooming and the severity of lesions caused by such grooming. This confirms the critical role of this protein in OCD and pinpoints the importance of appropriate neuronal connections in the striatum.

Most studies of OCD have focused on genetic susceptibility and manipulation of the serotinergic and dopaminergic systems. This study is potentially very exciting, as it confirms what neuroimaging has suggested for the past number of years: the loop between the cortex and the striatum is significant to the etiology of OCD. Neuroimaging studies of those with PWS are scarce, but confirmation of a disruption in the cortico-striatal loop in individuals with PWS could help better understand and treat OCD-like symptoms in the syndrome. Welch and colleagues have elucidated a very elegant model of OCD-like behaviors in mice that has great potential to add to our understanding of OCD in humans and holds great promise for better understanding OCD-like symptoms in PWS.

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Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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