Chaos in the brain's navigation system
Among other physiological processes, potassium is required for muscle and nerve cell excitability. Potassium ions cross the outer cell membrane via a variety of ion channels and thereby generate electrical currents. Professor Thomas Jentsch's team at the Leibniz Research Institute for Molecular Pharmacology (FMP) and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin identified the genes encoding the potassium channel family KCNQ2-5 two decades ago and demonstrated that mutations in KCNQ2 and KCNQ3 can cause hereditary epilepsy in humans. Pharmaceutical companies were able to develop targeted anti-epileptic drugs as a result of this pioneering research.
Now, teams of molecular biologists led by Thomas Jentsch and neurophysiologists supervised by Alexey Ponomarenko (formerly a member of FMP, now professor at Friedrich-Alexander-Universität Erlangen-Nürnberg) have discovered that KCNQ3 may also play a role in Alzheimer's disease and other cognitive disorders.
KCNQ3 immunofluorescence in hippocampus, firing of a pyramidal cell in time (white traces, theta oscillations and spikes) and space (place fields of spike bursts, left, and of single spikes, right) in a Kcnq3 knockout mouse.
Internal map of the brain
Normally, the transmitter acetylcholine inhibits neuronal potassium flow, which is necessary for the cortex's excitability and thus for memory and attention. It is well established that Alzheimer's patients gradually lose this cholinergic neuromodulation.
The current study examined the role of KCNQ3 channels in the neuromodulation of the brain's navigation system. The so-called place fields, a discovery for which a Nobel Prize was awarded several years ago, serve as an internal space map for the brain. “We found how various signals generated by place cells under the control of KCNQ3 channels interact with brain rhythms to form precise spatial maps,” says Alexey Ponomarenko.
Chaotic signal transmission
Professor Thomas Jentsch's team generated gene-modified mice with a defective KCNQ3 channel.
The knock-out mice with a defective KCNQ3 channel generated by Thomas Jentsch's group revealed a different picture: whereas the activity patterns of place cells in healthy mice were structured in time and space, in knock-out mice, the synaptic transmission by single or nearly simultaneous multiple (burst) signals of place cells was disorganized. “When bursts are fired, they typically have a certain rhythm. In the mutants, on the other hand, the bursts are not controlled by the rhythm, but are fired at completely random times or phases of the rhythm, as Ponomarenko explains. "This effectively suppresses single action potentials and creates an imbalance in the activity patterns of place cells."
Recordings using 15 micrometers thin silicon probes implanted in the hippocampus of freely behaving rodents, together with optogenetic experiments, provided exciting insights into brain function. Additionally, the American colleagues demonstrated that the absence of the KCNQ3 channel resulted in a significant decrease in neuronal potassium currents (here M-currents).
New target for drug research
“While the data to date are insufficient to guide clinical applications, our findings suggest that the KCNQ3 channels could be a potential target for future drug research to treat Alzheimer's-type and other dementias,” Professor Ponomarenko emphasizes, “at least in the early stages, when place cells are likely still present but cholinergic neuromodulation has already subsided.”
Additional research is required to gain a better understanding of KCNQ3's role in the brain.
Further information
- Department Physiology and Pathology of Ion Transport, FMP
- Institute for Physiology und Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg
Literature
Xiaojie Gao et al (2021): Place fields of single spikes in hippocampus involve KCNQ3 channel-dependent entrainment of complex spike bursts. Nature Communications, DOI: 10.1038/s41467-021-24805-2
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KNCQ3-Immunofluoreszenz im Hippocampus, zeitliche (weiße Signalspuren) und räumliche (Ortsfelder von Salven, links, und von einzelnen Aktionspotenzialen, rechts) Feuerung einer Pyramidenzelle in einer KNCQ3-Knock-Out Maus. © Modified from Gao et al., 2021
Contacts
Prof. Dr. Alexey Ponomarenko
Institute for Physiology und Pathophysiology
Friedrich-Alexander-Universität Erlangen-Nürnberg
Tel.: +49 (0) 9131 85 29 30 2
alexey.ponomarenko@fau.de
Prof. Dr. Thomas Jentsch
Department Physiology and Pathology of Ion Transport
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Tel.: +49 (0) 30 94 06 29 61
jentsch@fmp-berlin.de
Silke Oßwald
Public Relations
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Phone +49 (0)30 94793 104
osswald@fmp-berlin.de
