Can Body Lipid Inhibitors Treat Mental Disorders?

A genetic disorder leads to an increase in bioactive lipids in the brain, resulting in an imbalance between excitation and inhibition in neural circuits and promoting mental disorders. However, treatment with an enzyme inhibitor that prevents the activation of lipids can restore balance and alleviate symptoms.

Increased levels of bioactive lipids produced naturally in the body, which affect excitatory transmission between brain cells, promote mental disorders. However, this mechanism can be rebalanced by treatment with an inhibitor that prevents the activation of these lipids in the brain. That is the result of a recent study on the correlation between synaptic lipid signals in the brain and mental disorders. The results of the study ‘Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders’ have now been published in Molecular Psychiatry and could create new opportunities for the treatment of mental illness.

The 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 investigated 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. The research was carried out within the framework of Collaborative Research Centre 1451 ‘Key Mechanisms of Motor Control in Health and Disease’ (speaker: Professor Dr. Gereon Fink, University of Cologne).

The project under the leadership of Vogt and Nitsch within the CRC deals with the balance between excitation and inhibition in the brain and its effect on motor function. This balance plays an important role in mental disorders. In the case of excitation, neural circuits cause information to be passed on and other neurons to be activated; in the case of inhibition, this information transfer is interrupted.

The project groups in Cologne and Münster had already shown in previous studies that the body’s own lipids in the brain are activated by the enzyme autotaxin and stimulate nerve cell activity at the central checkpoint of signal transmission, the cortical synapse. As a result, they alter information processing in the brain’s networks.

In the current study, the researchers analyzed the functional consequences of altered signal balance in 25 individuals induced by the antagonist of autotaxin, which reduces the activated lipids at the synapse. Using various methods for measuring brain waves and brain activity as well as psychological tests, they found specific changes that also occur in patients, so-called intermediate phenotypes of mental disorders. This means, for example, that comparable patterns of brain activation can be found in both patients and their clinically healthy relatives.

Additional studies in the mouse model revealed that animals with a similar genetic disorder showed comparable symptoms: increased anxiety, a depressive phenotype, and lower stress resilience. Synchronization and information transfer between brain areas were similarly altered in humans and mice. “The study indicates that the regulation of excitation and inhibition by synaptic lipid signals plays a crucial role in the development of mental disorders,” said Professor Vogt.

Autotaxin is the key enzyme of lipid activation in the brains of mice and humans. The increased excitation state of the networks caused by the genetic disorder could be restored by administering specific inhibitors of autotaxin. According to the researchers, these findings open up new perspectives for the diagnosis and treatment of such disorders. “Targeted modulation of synaptic lipid signals using autotaxin inhibitors that can reach the brain could open up possibilities to treat mental disorders,” concluded Professor Nitsch. In future studies, the researchers plan to further investigate these approaches and to test their effectiveness and safety in clinical trials.

Autotaxin, an enzyme crucial for the activation of lipids in the brain, plays a significant role in maintaining the balance between excitation and inhibition within neural circuits. The disruption of this balance, often due to genetic disorders, can lead to various mental disorders. The enzyme’s counterpart, PRG-1, works to inhibit autotaxin, helping to maintain neural stability. When this balance is disrupted, the resulting increase in bioactive lipids leads to heightened excitatory signals, which can manifest as symptoms of anxiety, depression, and other mental health issues.

In their study, the researchers focused on understanding how the imbalance caused by increased lipid signaling could be rectified. They utilized a specific inhibitor that targets autotaxin, preventing it from activating these lipids. This approach effectively restored balance within the neural circuits, alleviating symptoms associated with the genetic disorder in both human and mouse models. The findings suggest that controlling lipid signaling at the synaptic level could be a viable therapeutic strategy for managing mental disorders.

The researchers employed various methodologies to assess the impact of altered lipid signaling on brain function. These included brain wave measurements, brain activity scans, and psychological tests. The results consistently showed that the inhibition of autotaxin led to significant improvements in neural synchronization and information transfer between brain regions. These improvements were observed in both human subjects and genetically modified mice, underscoring the potential of autotaxin inhibitors as a treatment for mental health conditions.

One of the critical aspects of the study was the identification of intermediate phenotypes of mental disorders. These phenotypes represent specific changes in brain activity and behavior that are common among individuals with similar genetic backgrounds. By targeting these intermediate phenotypes, the researchers could better understand the underlying mechanisms of mental disorders and develop more precise treatment strategies.

The role of autotaxin and PRG-1 in regulating neural balance is a complex but crucial aspect of brain function. Autotaxin’s ability to activate lipids at synapses directly influences excitatory signaling, which, when unchecked, can lead to mental health issues. PRG-1 serves as a natural counterbalance, inhibiting autotaxin and helping to maintain neural stability. Understanding this dynamic is essential for developing effective treatments for mental disorders that arise from lipid signaling imbalances.

Future research will focus on further elucidating the mechanisms by which autotaxin inhibitors exert their effects and determining the long-term safety and efficacy of these treatments in clinical trials. The ultimate goal is to develop targeted therapies that can address the root causes of mental disorders, offering patients more effective and personalized treatment options.