Novel Synaptic Plasticity Mechanism Revealed

Hebbian plasticity suggests that if connected neurons are active at the same time, the strength of the synaptic connection between them will be enhanced. This led to the adage, “those that fire together, wire together.”

However, new evidence from Jeff Magee’s lab, then at Janelia Research Campus and now at Baylor College, Tx, shows that synaptic plasticity in an area important for learning and memory, and spatial navigation, may not strictly conform to Hebb’s postulate.

Published in Science today, Bittner et al. describe a new type of long-lasting synaptic plasticity, Behavioural Time Scale Plasticity (BTSP).

Using electrophysiological techniques to record from brain cells in mice running on a treadmill and then using computer modeling to confirm their findings, they show that the window in which synaptic potentiation can occur in neurons important for spatial navigation spans seconds.

As co-lead author Katie Bittner describes, "BTSP is a form of plasticity where synaptic inputs that are active seconds before and approximately a second after a dendritic plateau potential (a large dendritic signal) are strengthened." explaining, "This is fundamentally different from the traditional form of synaptic plasticity where inputs are strengthened if they are active milliseconds before a postsynaptic action potential - or rather neurons that 'fire together, wire together.'"

Adding, "In this case, inputs do not need to cause the neuron to fire in order to be strengthened. They just need to be correlated with a dendritic event during a large time window."

As Katie mentions, these findings are in stark contrast to the specific millisecond bursts currently thought to be necessary to induce synaptic strengthening in these cells which exist in the CA1 region of the hippocampus.

Cells in this area fire with a characteristic complex spiking pattern when the animal is in a certain point in space, its place field, and they underlie the ‘GPS’ system of the mouse.

The researchers show that the electrical excitability of these cells ramps up as the mouse approaches its characteristic point at which it fires in space, and then ramps down from this plateau as it moves away. If a presynaptic input is active during this ramping it can lead to a spike and a potentiation of the synaptic communication. Meaning BTSP can rapidly store or integrate the entire sequence of spiking events that occurred for several seconds before and after the complex spiking in the CA1 neurons. Meaning cells that fire apart, can actually wire together.

This mechanism could mean that the place fields of the hippocampus can be adapted as the mouse experiences new features of the environment as it explores, and BTSP could facilitate this. 

Importantly, this type of plasticity allows for relevant environmental cues to be incorporated together as the mouse explores at speed. The excitability ramp broadens as more upstream cells and their synaptic inputs to CA1 cells are activated as the mouse runs through its environment incorporating more information than at a slower speed. Traditional Hebbian plasticity could not account for this. 

As co-author Aaron Milstein explains, "In our study, we found that dendritic plateaus lead to the association of sensory events in a fixed seconds-long time window. When the mouse was running fast, more distance was covered in the fixed time window, so more neurons that represent more spatial locations became associated." Which means more information is integrated as the mouse navigates its environment.

As Katie confirms, "The fixed time window for the plasticity means that during learning, if you're running, an individual neuron's place field will cover a larger distance, if you're walking the neuron's place fields will be more narrow."

And Aaron further emphasizes, "If you were driving fast in a car, you might see a sign on the road a few seconds before a turn, and it will remind you to turn, whereas if you were walking slowly, you might not recognize the turn until you are much closer to the decision point.

The researchers also performed classical pharmacology experiments on the CA1 neurons to investigate which channels in their cell membranes were responsible for inducing this type of plasticity, and they found that blocking a class of synaptic receptors called NMDA receptors and a type of channel which allows calcium into the cell prevented the formation of BTSP. They even perfused a calcium channel blocker onto the cells whilst the mouse was running on the treadmill to remove the ramp in vivo. 

The relevance of this new type of plasticity is still in question, and the reasons for this are described in Julia Krupic’s informed summary of the piece in the same edition of Science. Why the cells should need this type of plasticity, and why the synaptic inputs incorporated into the firing pattern can come from unrelated cues remains a mystery. The group suggest that the “BTSP induction mechanism may operate as an instructive-type signal, promoting learning that is neither autonomous nor correlative.”

As Katie explains, "BTSP allows single neurons to store information about a sequence. Inputs that don't directly cause the postsynaptic neuron to spike can still be strengthened depending on their temporal correlation with a dendritic plateau. This plasticity can happen in a single trial - which may allow for learning during a single experience."

And Aaron adds, "The slow time scale of BTSP (many seconds) is exactly what the brain needs to associate sequences of sensory events, like sights or sounds that predict a delayed reward. Also, this form of plasticity can completely change the information that a neuron has stored about the environment in a single shot, without any repetition. This feature is required by the brain to store memories of single episodes, or to learn from a single example."

Either way, this work provides the ground-truth in terms of the electrical activity of these neurons as the mouse navigates in space, even if we still don’t understand why.