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Mice Provide Important Clues To Obsessive-compulsive Disorder

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Mice born without a key brain protein compulsively groom their faces until they bleed and are afraid to venture out of the corner of their cages. When given a replacement dose of the protein in a specific region of the brain, or the drugs used to treat humans suffering from obsessive-compulsive disorder (OCD), many of these mice seem to get better.

SAPAP3 knockout mouse has a raw bald patch on its face from compulsive grooming behavior. (Credit: Guoping Feng, Ph.D., Duke University)

Duke University Medical Center investigators, in their basic research into how individual brain cells communicate with each other, discovered serendipitously that mice with a genetic mutation that prevents their brain cells from producing one key protein exhibited OCD-like behavior.

The finding may have uncovered important clues about a possible mechanism for OCD, a debilitating psychiatric condition affecting up to 2 percent of the world’s people.

The international team of researchers, led by Duke molecular geneticist Guoping Feng, Ph.D., reported its findings in the August 23 issue of the journal Nature. The research was supported by the National Institutes of Health, the McKnight Endowment Fund for Neuroscience, and the Hartwell Foundation.

“The mice that could not produce this protein exhibited behaviors similar to that of humans with OCD, a compulsive action coupled with increased anxiety,” Feng said. “We obviously cannot talk to mice to find out what they are thinking, but these mutant mice clearly did things that looked like OCD.”

OCD is one of the most common psychiatric disorders in the world. It is marked by persistent intrusive thoughts (the obsession), repetitive actions (the compulsion) and anxiety. The severity OCD varies widely from person to person, and while the neurobiological basis of the disease is unknown, there are indications that genetics play a role, Feng said.

In their experiments, the Duke team focused on a portion of the brain known as the striatum, an area that controls the planning and execution of movement, as well as other cognitive functions. It is in many ways “the decider.” In normal brains, a protein known as SAPAP3 is crucial for nerve signals to travel from one nerve cell to another across the synapse, the gap between the cells.

“This protein is important for allowing messages to cross synapses, and it is produced at high levels in the cells that make up the striatum,” Feng explained. “When we looked closely at the brain cells of these mutant mice, we found that there were defects in the synapses.

“When we returned the protein into the striatum of brains of the mutant mice, the synaptic defects were repaired and their OCD-like behaviors subsided,” Feng continued. “This is the first direct evidence that a synaptic defect in the striatum caused these OCD-like behaviors.”

The researchers also found that a class of drugs known as selective serotonin reuptake inhibitors (SSRI) reduced the anxiety levels and suppressed the over-grooming in the mutant mice, further suggesting that what they observed in mice may also be analogous to human OCD. Serotonin, like SAPAP3, is one of many neurotransmitters, chemicals involved in nerve cell communication.

While SSRIs are the most commonly prescribed drug for humans with OCD, they are only effective for about half the patients, suggesting to Feng that many pathways involving different neurotransmitters are likely involved.

Feng and other colleagues at Duke are currently looking for additional gene variations that may affect how nerve signals cross synapses, and they are also beginning studies to determine if the gene mutant they discovered in mice plays a role in humans with OCD.

Nature. 2007 Aug 23;448(7156):894-900.

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

Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, Feng G.

Department of Neurobiology, Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA.

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) 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 behaviour leading to facial hair loss and skin lesions; both behaviours 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 behavioural 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 behaviours.

PMID: 17713528 [PubMed – in process]


Written by huehueteotl

August 27, 2007 at 8:54 am

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