A genetic issue causes an excess of bioactive lipids in the brain, which creates an unbalance between excitation and inhibition in neural circuits and contributes to mental disorders. Nevertheless, using an enzyme inhibitor that stops the activation of lipids can bring back balance and ease symptoms.
Higher concentrations of bioactive lipids that are naturally produced in the body can impact the transmission of excitatory signals between brain cells and can contribute to mental disorders. However, this process can be restored to a more balanced state by using a treatment that blocks the activation of these lipids in the brain. These findings come from a recent study that examined the relationship between synaptic lipid signals in the brain and mental disorders. The results of this study, titled “Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders”, have been published in Molecular Psychiatry and may open up new possibilities for treatment.Opportunities for treating mental illness are being explored by teams led by Johannes Vogt (MD) at the Department of Molecular and Translational Neurosciences at the University of Cologne, Robert Nitsch (MD, PhD) at the Institute of Translational Neuroscience at the University of Münster, and partners at other universities. Their investigation focused on the role of the enzyme autotaxin and its opponent, the protein PRG-1, in regulating the balance between excitation and inhibition in the brains of humans and mice. This research was conducted as part of the Collaborative Research Centre 1451 ‘Key Mechanisms of Motor Control in Health and Disease’ (speaker: [speaker’s name]).Professor Dr. Gereon Fink from the University of Cologne is leading a project with Vogt and Nitsch in the CRC. The project focuses on the balance between excitation and inhibition in the brain and how it affects motor function, which is important in mental disorders. Excitation involves the transfer of information and activation of neurons, while inhibition interrupts this information transfer. Previous studies by the project groups in Cologne and Münster have demonstrated that the brain’s own lipids are activated by the enzyme autotaxin and stimulate neurotransmission.Investigating cell activity at the central checkpoint of signal transmission, the cortical synapse, changes the way information is processed in the brain’s networks.
The researchers in this current study examined the functional effects of altered signal balance in 25 individuals induced by the antagonist of autotaxin. This antagonist reduces the activated lipids at the synapse. Using a variety of methods to measure brain waves and brain activity, as well as administering psychological tests, the researchers discovered specific changes that also appear in patients with intermediate phenotypes of mental disorders. This suggests that comparable patterns of brain activity and function have been identified.Activation can be discovered in both patients and their clinically healthy relatives. Further research in mice also showed that those with a similar genetic disorder exhibited similar symptoms: heightened anxiety, a depressive phenotype, and reduced stress resilience. The coordination and exchange of information between brain regions were also affected in both humans and mice. Professor Vogt stated, “The study suggests that the control of excitation and inhibition by synaptic lipid signals is crucial in the development of mental disorders.” Autotaxin is the main enzyme of lipid activation in the brains of mice and humans.The researchers discovered that specific inhibitors of autotaxin could reverse the heightened excitation state in networks caused by the genetic disorder. This breakthrough could lead to new possibilities for diagnosing and treating these types of disorders. Professor Nitsch concluded that targeting synaptic lipid signals with autotaxin inhibitors that can penetrate the brain may offer new options for treating mental disorders. Future studies will delve deeper into these approaches and assess their effectiveness and safety in clinical trials.
