Posted: 10th October 2019
This year’s theme for World Mental Health Day – Do you see what I see?, is quite fitting, as our scientists strive to gain a better understanding of what causes mental health disorders, and why current treatments work, so that we can find ways to better treat or prevent them. We feel this is the best way SVI can lend our support to all those Australians who experience mental health disorders.
Since Australian psychiatrist John Cade employed lithium to successfully treat one of his bipolar patients in the 1940s, scientists have tried, and largely failed, to understand why the treatment is so effective. The difficulty stems from the fact that lithium interacts with many proteins and other molecules in the brain, making it hard to determine which interaction is responsible for its mood stabilisation effects. This is also the root of lithium’s undesirable and toxic side effects.
Dr John Scott, Leader of the Neurometabolism Team at SVI, became interested in the role of lithium because of his focus on the pathways that control memory, mood and emotional behaviour in the brain. His particular focus is a protein called Calcium-calmodulin-dependent protein kinase kinase 2 (CaMKK2).
“CaMKK2 is involved in transmitting the electrical signals in the brain that controls our mood and behaviour. A couple of years ago we became interested in mutations in CaMKK2 in people who are affected by with mental health disorders such as anxiety, bipolar and schizophrenia.”
John and his team showed that when they mimicked the human CaMKK2 mutations in the test-tube, the ability of CaMKK2 to transmit electrical signals was reduced.
John says, “We basically found a ‘switch’ in the protein that is normally able to be turned on and off. In people with mutations in CaMKK2, this switch is permanently off. Excitingly, we were able to show that treatment with lithium could overcome the effects of the mutation.”
“Our hypothesis is that at least one of the ways that lithium works is by creating a bypass of the defective circuit, essentially leapfrogging the broken switch.”
In order to prove this hypothesis John needed to create a genetically modified mouse in which the CaMKK2 switch was mutated in a similar fashion. His goal was to show that this one isolated change would result in similar behavioural changes as seen in humans with the mutation.
John has examined the effects of the mutation on the behaviour of his mice and is a step closer to his goal of understanding how lithium works, with a longer-term aim of developing safer and more effective therapies for debilitating mental health disorders.