Hansel Lab illustrates dendrites on cells in the cerebellum are more than mere bystanders

On the cartoon version of a neuron, the dendrites are the bad hair day, the tentacles that sprout in every direction from the cell body or soma. Surrounding neurons make their connections onto these projections, releasing neurotransmitters that travel across the synapse to the receiving dendrites where they produce excitation or inhibition. Thousands of these signals could be incoming at any given moment over the entire tree of a single cell’s dendrites, and those messages come together in the soma to determine the neuron’s subsequent action.

Classically, the dendrites are thought to be simple telephone operators of this information, just passing signals along to be dealt with at headquarters in the soma. But a new study in Neuron by University of Chicago scientists suggests that dendrites on cells in a brain region called the cerebellum are more than mere bystanders.

“People are starting to give much  more weight to dendrites,” said Christian Hansel, professor of neurobiology and senior author of the paper. “Before, they were considered like big antennae that collect electrical information coming in and passively funnel it down to the soma. Now, people have found that dendrites can are much more actively engaged. There is much, much more going on in the dendrites that is highly interesting.”

Part of the reason that dendrites were underestimated for so long is because they are so difficult to study. While the neuron’s soma is big, round and fat, dendrites are short, skinny, and tapered, and thus harder to stab with the neurobiologist’s favorite tool: the electrophysiology electrode. Much of what we know about neurons is from recording their electrical activity with these electrodes, which is typically done in the soma. But Hansel’s laboratory is one of only a handful in the world capable of recording from dendrites, which allows them to assess the role these dendritic branches play in synaptic plasticity and learning.

The Neuron paper is a sequel to a 2010 publication in the Journal of Neuroscience that was the first to describe a new type of cellular change in the cerebellum called intrinsic plasticity. The best known types of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), where synapses are made stronger or weaker when two cells fire in tandem. Unlike those cooperative mechanisms, the cerebellar intrinsic plasticity discovered by Hansel’s lab (recording from cell soma, in this case) was a one-neuron show. If a neuron called a Purkinje cell was stimulated with a burst of electrical spikes, it would remain in a hyper-excitable state for up to an hour — for as long as the researchers could record from it. But while the cell shifts into a higher gear, it also becomes resistant to the induction of LTP, suggesting that these two mechanisms are somehow linked.

“The results suggested that intrinsic plasticity is maybe part of a more sophisticated learning process, one that goes hand in hand with synaptic plasticity,” Hansel said. “That is what we wanted to find out.”

For the new experiments, Hansel and co-authors Gen Ohtsuki, Claire Piochon, and John Adelman looked even closer at Purkinje cells, focusing in on intrinsic plasticity within the dendrites. By recording simultaneously from both the dendrite and the soma of the same cell (no simple task), the researchers found that the same stimulating burst increased the excitability locally in the dendrite. They also confirmed that the SK channel, a potassium ion channel activated by the presence of calcium, was involved in this fine-tuning effect in the dendrites. Experiments revealed that the change in intrinsic excitability was mediated by a reduction in the function of the SK channels, which normally act to keep the dendrite calm.

“These SK channels are particularly interesting because they have this really unique ‘brake’ function in dendrites,” Hansel said. “What we describe here is a way to modify that brake in an experience-dependent, use-dependent manner, which is a criterion for these kinds of plasticity processes involved in learning. If you can modify this brake mechanism, and you can do that even in this branch-specific way that we showed, this is of course an extremely powerful tool that allows you to manipulate a cell in a much more sophisticated way.”

To illustrate that power, imagine the neuron not as a cloud of antennae, but as a mixing console at a concert.

Different microphones pick up their instruments at their native volume, but the sound engineer can control the volume of each channel by pushing a slider up or down. In the case of a neuron, the dendrites themselves can adjust the “volume” of incoming signals before sending them down to the cell soma. Further experiments revealed that these changes happen with astonishing specificity, as calcium-sensitive dye experiments showed that intrinsic plasticity could occur at one dendritic “spine” (an area where synapses are formed) without happening at another only 30 microns, or three-hundredths of a millimeter, away.

It’s not entirely clear yet what exact role this dendritic plasticity plays in learning. Because the cerebellum is largely involved in motor function, one would predict that the mechanism is an important part of motor learning — a hypothesis that upcoming experiments using an SK channel knockout mouse model will address. In the meantime, Hansel proposes that the intrinisic plasticity is a cellular instrument to tip the balance between the opposing forces of LTP and LTD.

“My favorite interpretation would still be that LTD is involved in cerebellar learning but LTP is just the other side of the same coin. You need both the learning and the reversal mechanism,” Hansel said. “You also need this amplification, because it just adds more to the complexity of the players involved. So you can now shift balances of LTP and LTD by shifting the probabilities for LTP and LTD induction. That means you can fine-tune the process…in a way that we don’t fully understand yet.”

Furthermore, because the brain tends to recycle tricks from one area to another, Hansel expects that this adjustable dendritic “brake” is unlikely to be an exclusive feature of the cerebellum. In fact, researchers have found intrinsic plasticity in the hippocampus, another brain area implicated in learning and memory, though haven’t yet determined whether it is mediated by the same SK channels used by cerebellar neurons.

“This mechanism might be just part of one big arsenal or toolbox that allow for this kind of compartment-specific modification,” Hansel said. “Potentially, I would think those would be mechanisms that can also be found in other brain areas.”

(see press release)