Dopamine is perhaps the best known neurotransmitter, almost certainly due to its association with the idea of reward. It’s often brought up to explain why we like the things we do, and how people can develop addictions to different types of rewards. However, dopamine isn’t just a reward chemical; it’s very important for a wide variety of brain processes, including voluntary movement, attention, sensory gating, evaluating the salience of a stimulus, decision making, and motivation. Given all this chemical does, it’s not too surprising that changes in dopamine signaling have been implicated in mental disorders, like schizophrenia, ADHD, and depression. But how, then, does a healthy brain regulate dopamine? And how does this system go wrong?
Larry Zweifel’s lab at the University of Washington studies these questions. Soden et al. examined the effect of a mutation in a gene called KCNN3 that was discovered in a schizophrenia patient (Bowen et al., 2001). This gene codes for an ion channel called SK3 that is activated when calcium is inside the cell and then lets potassium out of the neuron, reducing its excitability. The mutated form, however, has an early stop codon due to a frame shift, and therefore only produces a small fragment of the original protein. Interestingly, this mutation was found to be dominant in cell culture, needing only one copy to exert its full effect and suppress SK3 currents in neurons, likely because the protein fragments bind to and inactivate SK3 channels (Miller et al., 2001).
Since SK3 is expressed in dopamine neurons and was mutated in a schizophrenia patient, it seems a promising candidate for a gene regulating dopamine function. Soden et al. tested the effect of this mutation in a mouse model by adding the mutated gene into the genome of dopamine neurons using a viral vector and the Cre-lox system. Indeed, they found that dopamine neurons in the mice with the mutant gene were more excitable and fired less regularly than usual, making them more prone to firing bursts of action potentials.
These bursts are thought to be a functionally different form of dopamine signaling than the neurons’ regular spiking, causing different effects in dopamine-responsive brain regions, so this altered neuronal function should correspond to altered behavior in tasks where dopamine is important. Since dopamine is involved in sensory gating, meaning the brain’s filtering of irrelevant stimuli, the researchers tested this ability in the mutant mice. In their task, the mice were presented with two sounds, one which was was always followed by a reward (a sugary pellet), and one which was rarely followed by a reward. The mice learned to look for the pellet quickly after the more predictive sound, but not after the other. Once the mice had learned to distinguish the sounds, the researchers flashed a light at the same time the reward-predictive sound was played. The normal mice became distracted, but the mutant mice paid no attention to the novel stimulus and still proceeded quickly to the pellet, indicating that their sensory gating was altered.
The researchers also tested their mice on prepulse inhibition (PPI), a neurological process by which the startle response of an animal to a sudden, high amplitude stimulus, such as a loud sound, is reduced if the strong stimulus is preceded by a weaker one. This phenomenon occurs in both mice and humans, is affected by dopamine-modulating drugs, and is reduced in people with schizophrenia. Indeed, the control mice showed prepulse inhibition, while the mutant mice did not.
This paper is significant in that the authors were able to demonstrate a link across multiple levels of biology, from disrupted gene function to neuronal function to behavior. As the KCNN3 gene is in a chromosomal region (1q21) that is associated with schizophrenia, it’s possible that this gene, and pathological processes similar to that shown here by the author, are at play in more cases of schizophrenia. The ability understand how the brain is disrupted across different scales in psychiatric illness is crucial to developing better, targeted treatments for these conditions.