For our brain to generate precise spatial maps, the potassium channel KCNQ3 is essential. If the channel is defective, this has measurable effects on the internal navigation system of mice. The findings of a research team including the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin, now published in Nature Communications, are also relevant for Alzheimer’s research.
Among other things, potassium is essential for the excitability of muscle and nerve cells. Various ion channels ensure that potassium ions flow across cell membranes, thereby generating electrical currents. Twenty years ago, Prof. Thomas Jentsch’s team at the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin identified the genes for the KCNQ2‑5 potassium channel family and later showed that mutations at KCNQ2 and KCNQ3 can cause hereditary epilepsy in humans. This groundbreaking work has enabled pharmaceutical companies to develop targeted antiepileptic drugs.
Now, a team of molecular biologists led by Thomas Jentsch and a team of neurophysiologists led by Alexey Ponomarenko (formerly of the FMP, now a professor at Friedrich Alexander University Erlangen-Nuremberg), together with colleagues at the University of Connecticut and the University of Cologne, have found evidence that KCNQ3 may also play a role in Alzheimer’s dementia and other cognitive disorders.
Normally, certain potassium currents are inhibited by the transmitter acetylcholine, which is important for excitability in the cortex and thus crucial for memory and attention. This so-called cholinergic neuromodulation is known to be gradually lost in Alzheimer’s patients.
In the present work, the researchers investigated the role of KCNQ3 channels specifically in neuromodulation of the brain’s navigational system. The so-called place fields (“place fields”), whose discovery won the Nobel Prize a few years ago, serve as the brain’s internal map.
“We found how different signals generated by place cells under the control of KCNQ3 channels interact with brain rhythms to form precise spatial maps.”
- Alexey Ponomarenko
However, knock-out mice with defective KCNQ3 channels generated by Thomas Jentsch’s group showed a different picture: While in healthy mice the activity patterns of place cells were subject to a specific spatial and temporal sequence, in the knock-out mice the synaptic transmission of single or multiple signals simultaneously (volleys) proceeded more or less chaotically.
“Salvos normally have a specific rhythm as to when they are fired. In mutants, however, they are no longer controlled by the rhythm, but are fired at completely random times or phases of the rhythm,” Ponomarenko explains. “As a result, individual action potentials are suppressed and there is an imbalance between different patterns of activity in the neurons.”
15-micrometer-thin silicone electrodes implanted in the rodents’ hippocampus, together with optogenetic studies, provided the exciting insights into the brain. The American colleagues were also able to show that the missing KCNQ3 channel led to a strong reduction in potassium currents (M‑current in this case) in the neurons.
“Although the data available so far are not sufficient for clinical application, our findings suggest that KCNQ3 channels could be a potential target for future drug discovery against Alzheimer’s disease and other dementias,” Prof. Ponomarenko emphasizes, “at least in the early stage, where place cells are probably still present but cholinergic neuromodulation has already subsided.” Further studies will now follow to further understand the role of KCNQ3 in the brain.
