Roughly 2% of humans suffer from obsessive compulsive disorder, but a lack of animal models has impeded research into this condition. Could a genetically engineered mouse model provide an exciting lead?And, a word of caution:
The mice studied by Welch et al. showed excessive grooming, which resulted in hair loss and skin injuries, as well as anxiety-like traits. These mice lack the gene encoding SAPAP3 — a scaffolding protein that is found in excitatory, glutamate-responsive synapses and is highly expressed only in the striatum region of the brain. The behavioural abnormalities in these mice were reversed by local expression of Sapap3 in the striatal region, which indicates that loss of this gene is responsible for the observed behavioural abnormalities.
The authors also found that a drug from the SSRI class — which selectively enhance serotonin-mediated neurotransmission throughout the brain — that is used to treat OCD in humans decreases both grooming and anxiety in these mice. This is interesting because a condition responsive to an enhancer of serotonin neurotransmission does not signify a primary defect in serotonin-mediated signalling; instead, the defect is in glutamate-responsive synapses. So alterations in serotonin seem to modulate glutamate action. These findings are also noteworthy because Welsh and colleagues have generated a possible mouse model of OCD. Moreover, these observations add to the accumulating, if circumstantial, evidence that OCD and its associated disorders result from abnormalities in neural circuits spanning the frontal, striatal and thalamic regions of the brain.
Even if we can gain assurance with additional research that the behaviours observed in Sapap3-deficient mice reflect abnormalities in circuits that produce human symptoms, we cannot assume that OCD-related conditions in humans involve variations in this gene. These disorders, like other major psychiatric diseases, seem to be heterogeneous with complex underpinnings — probably involving several genes — that, in interaction with developmental and environmental factors, could lead to abnormalities in frontal–striatal–thalamic circuits.