Mechanism Behind Neurons’ Autonomous Excitability Revealed

To send and receive messages in the brain, neurons can autonomously fine-tune their sensitivity to certain signals. The accumulation of these signals results in action potentials, or rapid changes in the neuronal membrane voltage, and ultimately, the message is relayed to its destination. Researchers from the University of Bonne and the University Hospital Bonne decided to investigate this complex, autonomous mechanism in their work, published in the journal Cell Reports.  

“The neurons in the cerebral cortex are stimulated by the signals from the thalamus to generate action potentials,” says senior author Prof. Dr. Heinz Beck from the Institute of Experimental Epileptology and Cognition Research at the University Hospital Bonn. “These are short voltage pulses that are then transmitted to other sites in the brain. For that to work well, the neurons have to adjust to the intensity of the excitatory signals.”

Maintaining an appropriate balance between excitation and inhibition is crucial for neuronal information processing and can be adjusted on a case-by-case basis. For example, cells can dial down their sensitivity if incoming stimuli are particularly strong. “We have now discovered that a specific enzyme called SLK plays a role in this process,” says Beck, who is also a spokesperson for the Transdisciplinary Research Area “Life and Health” at the University of Bonn. “It enables neurons to individually calibrate their own excitability.”

The team describes a Ste20-like kinase (SLK) that mediates cell-autonomous regulation of the balance between excitation and inhibition in the thalamocortical feedforward circuit. Additionally, computational modeling revealed that this mechanism promotes stable excitatory-inhibitory ratios across pyramidal cells, a common source of intrinsic excitatory cortical synapses within the cerebral cortex.

“In this mechanism, special nerve cells play an essential role, the so-called interneurons,” explains first author Dr. Pedro Royero from Beck’s research group. “The SLK now determines how much this regulator can be adjusted by the interneurons, that is, how strong their inhibitory effect is.”

There are two primary types of interneurons – some are activated directly by incoming impulses from the thalamus, while others are only switched on by neuronal activity in the cerebral cortex. These neurons are part of a negative feedback loop. “Interestingly, the SLK is not active in this feedback inhibition, but only in the first case,” Royero explains.

The team also discovered that specific genes activate during sensitivity adjustment. For future work, they hope to examine their role in this process, particularly in cases of epilepsy, where characteristic seizures occur due to overexcitation of large areas of nerve cells. Some studies have shown that, in some epileptic patients, less SLK is found in neurons than usual, so the researchers hope to better understand these disease mechanisms.