Unlocking Memory’s Secret: How a Tiny Protein Gets Moving to Boost Brain Power

Hey there, fellow brain enthusiasts! Have you ever wondered how our brains actually *remember* things for the long haul? It’s not just about storing information; it’s also about physically changing the connections between brain cells, those amazing neurons. Think of it like building stronger bridges between important places in a city. These bridges happen at tiny structures called dendritic spines – they’re like little receiving antennas on neurons. And for these antennas to work really well for long-term memory, they need some internal scaffolding and machinery, including something called the smooth endoplasmic reticulum, or sER for short.

For a while now, we’ve known that getting the sER to extend into these dendritic spines is a big deal for making those connections stronger and lasting, especially during something scientists call Late-phase Long-Term Potentiation (L-LTP). This L-LTP is a key process for learning and memory. We also knew that a protein called Septin 3 (SEPT3) was involved, acting like a guide or maybe even part of the track for the sER. And it needed a partner-in-crime, a motor protein called Myosin-Va (MYO5A), which hangs out on the sER. When calcium levels go up (a signal that the synapse is active!), SEPT3 and MYO5A team up.

But here was the puzzle: SEPT3 usually hangs back at the *base* of the spine, like a bouncer at the club entrance. MYO5A is on the sER, ready to roll. How does SEPT3 get from the entrance onto the dance floor (the sER membrane) inside the spine to help MYO5A pull the sER in? That was the mystery we needed to crack!

The Plot Twist: A Phosphate Tag!

Turns out, the brain has a clever way of telling SEPT3 when it’s time to move. It’s a process called phosphorylation – basically, adding a little chemical tag (a phosphate group) onto the protein. We suspected this might be the key because phosphorylation is like the brain’s favorite way to switch proteins on or off, or tell them where to go, especially during big events like the kind of stimulation that leads to L-LTP.

So, we rolled up our sleeves and did some experiments. We stimulated brain tissue from the hippocampus (a memory hub!) and looked at SEPT3. And bingo! We found that SEPT3 *does* get phosphorylated when you give it a jolt, the kind of jolt that mimics strong synaptic activity. This was our first big clue!

Finding the “Go” Switch

Okay, so SEPT3 gets phosphorylated. But *where* does this phosphate tag attach? Proteins are long chains of amino acids, and phosphorylation usually happens at specific spots, often on amino acids like serine, threonine, or tyrosine. We looked at potential spots on SEPT3 and created versions of the protein where we could either *mimic* phosphorylation (make it act like it’s always phosphorylated) or *prevent* phosphorylation at certain spots.

We put these different versions of SEPT3 into cultured brain cells, specifically the kind found in the dentate gyrus of the hippocampus – a region known to be important for forming new memories and where sER extension into spines happens during L-LTP. We watched what happened to the sER in the spines. And guess what? Only the version of SEPT3 that mimicked phosphorylation at a specific spot, Threonine 211 (Thr211), caused a big increase in the number of spines that had sER inside! The spines didn’t get bigger, which was interesting – it means SEPT3 phosphorylation is specifically about getting the sER *in*, not changing the overall spine shape dramatically at this step.

This was huge! It told us that phosphorylation at Thr211 is the specific signal that helps the sER get into the spine.

SEPT3 Changes Address

Now that we knew Thr211 phosphorylation was important for sER extension, we wanted to see *why*. Our earlier work showed SEPT3 was usually at the spine base but moved onto the sER membrane after strong stimulation. Did this phosphorylation event explain that move?

We tagged different versions of SEPT3 (the normal one, the one that *can’t* be phosphorylated at Thr211, and the one that *mimics* phosphorylation at Thr211) with a glowing marker (GFP) and watched where they went in the spines. Just as we thought, the normal SEPT3 and the one that couldn’t be phosphorylated stayed mostly at the spine base. But the SEPT3 that mimicked phosphorylation at Thr211? It showed up much more inside the spine, right where the sER is!

This confirmed our hypothesis: Phosphorylation at Thr211 is the signal that tells SEPT3 to leave the spine base and become available to work with the sER and MYO5A inside the spine.

The Dynamic Duo: Phosphorylated SEPT3 and Activated MYO5A

So, we have phosphorylated SEPT3 now inside the spine and available. We know MYO5A is the motor on the sER membrane, and it gets activated when calcium levels rise during synaptic activity. Does phosphorylated SEPT3 team up with activated MYO5A to pull the sER in?

To test this, we used a version of MYO5A that’s *always* active (called MYO5A-CCtr – think of it as a motor stuck in the “on” position). We then combined this with our different SEPT3 versions. When we expressed the always-active MYO5A along with the normal SEPT3, we saw an increase in sER-containing spines, just like we’d seen before with strong stimulation. But when we paired the always-active MYO5A with the SEPT3 that *mimics* phosphorylation at Thr211 (T211E), we saw a similar, strong increase in sER in spines. This suggested that the T211E mutation was effectively replacing the need for the stimulation-induced phosphorylation step to get SEPT3 ready to work with MYO5A.

To really nail down that both are needed, we did experiments where we reduced the cell’s own SEPT3 levels and then tried to “rescue” the sER extension by adding back our modified SEPT3s and the active MYO5A. We found that you needed *both* the SEPT3 that could be phosphorylated (or the one mimicking phosphorylation) *and* the active MYO5A to get the sER into the spines efficiently. If SEPT3 couldn’t be phosphorylated at Thr211, even with active MYO5A, the rescue didn’t work as well. We also showed that blocking MYO5A activity prevented the sER extension even if SEPT3 was phosphorylated. It’s a true partnership!

And finally, we looked directly at whether phosphorylation at Thr211 makes SEPT3 stick better to MYO5A. Using biochemical methods, we found that the SEPT3 version mimicking phosphorylation at Thr211 *did* associate more strongly with MYO5A than the normal SEPT3. This makes perfect sense – once SEPT3 is phosphorylated and moves away from the spine base, it’s free to bind MYO5A on the sER and help it do its job.

The Big Picture for Your Brain

So, what does all this mean? We’ve uncovered a crucial molecular switch! When a synapse gets strongly activated (like during learning), SEPT3 gets phosphorylated at Thr211. This phosphorylation acts like a release signal, freeing SEPT3 from its usual spot at the spine base. Once free, phosphorylated SEPT3 can then team up with the activated MYO5A motor protein on the sER membrane. Together, this dynamic duo helps pull the sER into the dendritic spine.

Why is getting sER into spines so important? The sER is a major storage site for calcium. Having sER right there in the spine means calcium signals can be bigger and last longer. These robust calcium signals are absolutely vital for maintaining the structural changes and molecular events that underlie long-term synaptic plasticity and, ultimately, long-term memory.

Think of it this way: the initial learning event (L-LTP) triggers the phosphorylation of SEPT3. This allows SEPT3 to join forces with MYO5A, extending the sER into the spine. This physical change provides the necessary machinery (the sER’s calcium store) to keep that spine active and strong for a long time, helping you remember that important piece of information or skill.

It’s fascinating to think about how these incredibly tiny molecular events, like adding a single phosphate group to a protein, can have such profound effects on something as complex as memory. Understanding this mechanism gives us deeper insight into how our brains store information over time.

And looking even further ahead, this research opens up exciting possibilities. If we can understand exactly how to control this SEPT3 phosphorylation and sER extension, could we potentially develop ways to strengthen synaptic connections artificially? Could this knowledge lead to new therapies for conditions involving memory impairment? It’s the kind of fundamental discovery that sparks ideas for the future of neuroscience and medicine. It just goes to show, sometimes the biggest secrets are hidden in the smallest details, like a phosphate tag on a protein!

Source: Springer