SYNAPTIC DEFECTS IN OBSESSIVE-COMPULSIVE DISORDER
Obsessive-compulsive disorder [OCD, F42.8 (DSM-IV-TR) and 300.3 (ICD-10)] is characterized by persistent intrusive thoughts (obsessions), constrained repetitive activity (compulsions) and anxiety, which is only partially reduced by compulsions. The condition severely impairs lives of those affected and remains as an unresolved problem for psychiatric research. For decades OCD had been studied in a psychoanalytic perspective and only in recent years neurobiological research found some insights about underlying neurological deficit and its genetic background.
Mario Roberto Capecchi (2007 Nobel Prize for Physiology or Medicine) and his colleagues have shown that mice with targeted disruption of Hoxb8 exhibit a dramatic behavioural defect resembling rituals observed in OCD affected patients. These mutant mice show, with 100% penetrance, excessive grooming that leads to hair removal and self-inflicted wounds at those sites. Other functions and behaviours are normal and OCD-like grooming is not elicited by local irritation, and the most convincing evidence that the compulsion is not a response to local irritation is that when these mutants are placed together with wild-types littermates, the mutants also groomed the littermates to the extent of inducing hair loss.
Functional neuroimaging analysis of patients suffering from OCD has shown abnormal activity in the striatum, the orbital cortex, and the anterior cingulated cortex, which has become known as the OCD-circuit. Interestingly, Hoxb8 is strongly expressed in these regions of the central nervous system, as well as in regions previously implicated in the execution of grooming behaviour.
Feng, Welch and their colleagues generated transgenic mice in which a component of the excitatory post-synaptic density (PSD), SAP90/PSD95-associated protein 3 (SAPAP3), is lacking, and found that these mice displayed OCD-like behaviour (Welch J. M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894-900, 2007).
At 4-6 months of age, Sapap3-/- mice developed skin lesions as a result of excessive grooming, and testing their anxiety levels by several behavioural paradigms, researchers found heightened anxiety-like behaviour. A treatment of Sapap3-/- mice with a selective serotonin-reuptake inhibitor (a drug used in humans affected by OCD), for 6 days, reduced excessive grooming and anxiety-related behaviour.
When a lentivirus expressing Sapap3 was injected into the striatum, normal behaviour was also restored, confirming the role of striatal SAPAP3 for the obsessive phenotype.
Studying cortico-striatal synapses in brain slices from Sapap3-/- mice, Feng and his co-workers found anomalies in synaptic transmission mediated by AMPA and NMDA receptors, alterations in the levels of different NMDA-receptor subunits, and reduced thickness of PSD containing receptor layer.
This study provides evidence for a link between a specific cortico-striatal synaptic dysfunction and OCD-like behaviour, indicating a way for future work.