Ion Channel "Switches" Control Dopamine Release in the Brain

Scientists from the University of Washington (UW) School of Medicine have identified two ion channel “switches” in mice that regulate the release of dopamine in the brain. The research is published in Science Advances.

Ion channels and dopamine release

Cell membranes possess ion channels, which can be likened to “mini gates” controlling the flow of specific ions in or out of the cell. This movement of ions is important for many biological processes, including the maintenance of fluid balance, cell communication and the generation of action potentials in neurons.

Due to their role in action potential generation and neurotransmitter release, ion channels are attractive drug targets in neuropharmacology. The laboratory of Dr. Larry Zweifel, professor of psychiatry and behavioral sciences at the UW School of Medicine, has been working to understand which ion channels are involved in dopamine release regulation.  

Dopamine dysfunction is associated with a number of disorders, including schizophrenia, autism spectrum disorder (ASD) and addiction. “The ability to precisely manipulate how dopamine-producing neurons of the brain regulate different behaviors is a major step toward developing better therapies for a range of mental illnesses,” says Zweifel.

In the brain, dopamine is released in two distinct patterns: tonic firing, whereby dopamine is released slowly and levels are sustained, and phasic firing, where there is a “burst” of high-concentration dopamine release. These patterns are thought to contribute to dopamine’s function in reinforcement learning; however, the properties of the cell that result in patterning action potential firing are not well understood.

Deactivating one ion channel made mice smarter, turning off the other increased motivation  

Zweifel and colleagues hypothesized that two ion channels – Kv4.3, a type of potassium channel, and BKCa1.1, a type of calcium-activated potassium channel – are likely involved in dopamine release regulation [Updated, August 30, 2023]. The researchers used a genome-editing tool called CRISPR-Cas9 to selectively mutate the genes encoding the ion channels in dopamine-releasing neurons in mice. “We found that inactivation of Kv4.3 and BKCa1.1 differentially affected the action potential waveform, neuronal excitability, and patterns of action potential firing,” they explain in the paper.

“Loss of BKCa1.1 ion channel subunits in VTA dopamine neurons enhanced burst firing and phasic dopamine release that was associated with enhanced acquisition of instrumental behavior and a heightened extinction burst behavior,” the researchers describe. Once the mice learned the task, they were motivated to re-attempt it at a quicker pace. In contrast, loss of Kv4.3 resulted in transient high levels of dopamine triggered in response to specific stimuli, resulting in the mice learning faster.  

“This is what we've been working toward for some time: to understand how dopamine signals are regulated so that we can come up with better therapeutics. They may not target these specific channels, but now that we're beginning to get a handle on the mechanism, we might be able to find other players in the process that make for better targets,” Zweifel says.

While the study explored the role of Kv4.3 and BKCa1.1 in dopamine neurons, the research team emphasize that these channels are expressed widely throughout the human brain. “The emergence of many of these ion channels as hotspots of missense mutation in neurodevelopmental disorders reinforces the importance of understanding how these channels influence cellular and systems function,” they conclude.

Reference: Juarez B, Kong MS, Jo YS, et al. Temporal scaling of dopamine neuron firing and dopamine release by distinct ion channels shape behavior. Sci Adv. 9(32):eadg8869. doi: 10.1126/sciadv.adg8869

This article is a rework of a press release issued by the University of Washington School of Medicine. Material has been edited for length and content.

Correction

The article erroneously stated that the BKCa1.1 protein is a calcium channel, this was updated on August 30, 2023, to correctly identify BKCa1.1 as a calcium-actived potassium channel.