Posts Tagged ‘ synapses ’

The Memory Master

A gene that may underlie the molecular mechanisms of memory has been identified, says a new study.

Some of us feel that "yellow" and "red" are open to interpretation...

The gene’s called neuronal PAS domain protein 4 (Npas4 to its friends). When a brain has a new experience, Npas4 leaps into action, activating a whole series of other genes that modify the strength of synapses – the connections that allow neurons to pass electrochemical signals around.

You can think of synapses as being a bit like traffic lights: a very strong synapse is like a green light, allowing lots of traffic (i.e., signals) to pass down a particular neural path when the neuron fires. A weaker synapse is like a yellow light – some signals might slip through now and then, but most won’t make it. Some synapses can inhibit others, acting like red lights – stopping any signals from getting through. And if a particular synapse goes untraveled for long enough, the road starts to crumble away – until finally, there’s no synapse left.

There’s a saying in neuroscience: “Cells that fire together wire together.” (And vice versa.) In other words, synaptic plasticity – the ability of neurons to modify their connectivity patterns – is what allows neural networks to physically change as they take in new information.  It’s what gives our brains the ability to learn.

In fact, millions of neurons are delicately tinkering with their connectivity patterns right now, inside your head, as you learn this stuff. Pretty cool, huh?

Anyway, synaptic plasticity’s not exactly breaking news – scientists have been studying it in animals like squid and sea slugs since the 1970s. Neurons in those animals are pretty easy to study with electrodes and a microscope, because a) the animals are anatomically simple compared to humans, and b) some of their neurons are so huge they can be seen with the naked eye.

Studying synapses in humans isn’t quite so simple, though. For one thing, most people wouldn’t like it if you cut open their brain and started poking around while they were alive and conscious – and besides, a lot of the really interesting stuff happens down at the molecular level.

That brings up an important point: though you normally hear about genes in connection with traits – say, a “gene for baldness” and so on – these complex molecular strands actually play all sorts of roles in the body, from building cells to adjusting chemical levels to telling other genes what to do.

That’s why MIT’s Yingxi Lin and her team set out to study the functions of certain genes found in the hippocampus – a brain structure central to memory formation – the journal Science reports. The researchers taught a group of mice to avoid a little room in which they received a mild electric shock, then used a precise chemical tracking technique to isolate which genes in the mouse hippocampus were activated right when the mice learned which room to avoid.

In particular, they focused on a hippocampal region with the sci-fi-sounding name of Cornu Ammonis 3or CA3 for short:

We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning.

By “transcriptional program,” the paper’s authors mean a series of genetic “switches” – genes that Npas4 activates – which in turn make chemical adjustments that strengthen or weaken synaptic connections. In short, Npas4 appears to be part of the master “traffic conductor program” for many of the brain’s synapses.

Though they were pretty excited by this discovery (who wouldn’t be?) the researchers took a deep breath, calmed down, and double-checked their results, by testing memory formation in mice whose brains were unable to produce Npas4:

Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice.

In short, they make a pretty convincing argument that Npas4 is a necessary ingredient in a mouse’s ability – and probably our ability – to form certain types of new memories.

Exactly how that program relates to our experience of memory remains unclear, but it’s a promising starting point for fine-tuning future memory research. I don’t know about you, but I’d be thrilled to green-light such a project.

Synaptic Changes

Synapses – the junctions where neurons communicate – are constantly growing and pruning themselves – and those two processes occur independently of one another, says a new study.

A neuron shows off its fancy green glowy-ness.

As a synapse sees more and more use, it tends to grow stronger, while synapses that fall out of use tend to grow weaker and eventually die off. Collectively, these processes are known as synaptic plasticity: the ability of synapses to change their connective properties. But as it turns out, the elimination of redundant synapses isn’t directly dependent on others being strengthened – instead, it seems to be triggered by its own independent chemical messaging system.

Like many mammals, we humans are born with brains that aren’t yet particularly well-adapted for anything other than – well, adaptation. Through our brains’ extraordinary plasticity, we’re able to learn, in a few short years, everything from how to walk upright to how to argue – and as we grow older, our brains learn how to learn more quickly and think more efficiently by pruning away unneeded synapses.

But all that speed and flexibility come at a price: the balance between synaptic growth and die-back must be delicately maintained. Excessive connectivity can lead to diseases like epilepsy, while insufficient communication can result in disorders like autism.

This kind of summarizing oversimplifies the situation, of course – brain disorders rarely have just a single cause, or a clearly-defined set of symptoms. Even so, they provide grim reminders of the precise electrochemical balancing act that continues in the dark backstage of our skulls throughout each moment of every day.

And now, as the Journal of Neuroscience reports, a team led by The Jackson Laboratory’s Zhong-wei Zhang has found that synaptic growth and pruning aren’t two parts of a single process after all – they’re two processes, coordinated through two different chemical signaling systems.

The team discovered this by studying a certain type of glutamatergic synapses - i.e., synapses that use the common neurotransmitter chemical glutamate – in mouse neurons. The specific type of synaptic receptor the team studied is called the AMPAR, which is short for (get ready for this) “α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.”

The team discovered that when AMPARs of baby mice were deprived of glutamate stimulation, these receptors’ symapses didn’t grow stronger, as they did in normal mice:

Deletion of GluA3 or GluA4 caused significant reductions of synaptic AMPAR currents in thalamic neurons at P16–P17, with a greater reduction observed in GluA3-deficient mice.

No huge shock there. But what was surprising for the team was their other discovery – that even in these glutamate-deficient mice, pruning of AMPARs still proceeded normally:

Deletions of GluA3 or GluA4 or both had no effect on the elimination of relay inputs: the majority of thalamic neurons in these knock-out mice—as in wild-type mice—receive a single relay input.

Looking at this data, it’s hard to escape the conclusion that pruning of AMPARs is dependent on a separate mechanism from their strengthening. Just what that other mechanism is remains to be seen.

In short, this is another example of how even the most mundane workings of our brains continue to stun neuroscientists with brand-new revelations every day.

Silicon Synapses

A new kind of computer chip mimics the way a neuron learns, a new study reports.

Behold! The mighty Synapse Chip!

The 400-transistor chip simulates the activity of a single synapse – a connection between two neurons. Because of the chip’s complexity, it’s able to mimic a synapse’s plasticity – its ability to subtly change structure and function in response to new stimuli.

For example, a synapse that repeatedly responds to an electric shock might, over time, become less sensitive to that shock. Thus, synaptic plasticity forms the basis of neural learning, well below the level of conscious processing.

The human brain contains approximately 100 billion neurons, and more than 100 trillion synapses. Ever since the anatomist  Santiago Ramón y Cajal discovered the function of neurons back in the early 1900s, scientists have dreamed of building a device that replicated the behavior of even a single synapse. For decades, they had to content themselves with mathematical models and digital simulations.

But now, as the journal Proceedings of the National Academy of Sciences reports, a team led by MIT’s Chi-Sang Poon has constructed a working silicon model of a synapse in the physical world.

The chip uses transistors to mimic the activity of ion channels – small “ports” in the cell membranes of neurons that allow various amounts of neurotransmitter chemicals and ions (positively or negatively charged atoms) to pass in and out of the cell. These channels form the basis for synaptic communication – and for some of the most hotly researched topics in neuroscience.

While ordinary transistors act as binary “on/off” gates, neural synapses conduct signals along fairly smooth gradients, allowing the signals to increase in strength until they finally trigger the neuron to “fire” a signal on to its neighbor(s). It was this gradient property that Poon’s team sought to mimic with their new chip:

While most chips operate in a binary, on/off mode, current flows through the transistors on the new brain chip in analog, not digital, fashion. A gradient of electrical potential drives current to flow through the transistors just as ions flow through ion channels in a cell.

Since the researchers can also tweak the chip’s properties to mimic different kinds of ion channels, this provides one of the most realistic models yet for studying how individual synapses actually work.

The researchers have already used the chip to study long-term depression (LTD), the process by which some ion channels can weaken the synaptic activity of others. They also hope they’ll soon be using chips like this one in conjunction with lab-grown biological neurons, to discover all kinds of exciting new things about how cells behave “in the wild.”

Who knows – by this time next year, we may be watching nature documentaries about Neuron Cyborgs – but my guess is that the SyFy channel will get there first.

Brief and tangentially relevant side-note: Connectome posts may be somewhat spotty over the next few weeks, as I’m currently launching a new project, the details of which need to be kept under wraps (or “on the DL,” as the kids say) for the time being. I’ll do my best to report on neuroscience breakthroughs as often as I can during this period, and things should be back to (relatively) normal soon. Thanks for stickin’ with me.

Diff’rent Vesicles

A new discovery shows that the rules of synaptic transmission are very different from what we’d thought.

A synapse, blissfully unaware of the VAMP7s lurking in its midst.

In each neuron, tiny sacs called vesicles store neurotransmitter chemicals, and help transport them to other neurons. For decades, scientists had thought all the vesicles of a particular neurotransmitter were more or less identical – but now, they’ve discovered that only one set of vesicles are marked for transmission, while a much larger set lay mysteriously dormant.

What causes these differences, you ask? A protein with an awesome name:

We now find that the v-SNARE tetanus toxin-insensitive vesicle-associated membrane protein (VAMP7) differs from other synaptic vesicle proteins in its distribution to the two pools, providing evidence that they differ in molecular composition. We also find that both resting and recycling pools undergo spontaneous release, and when activated by deletion of the longin domain, VAMP7 influences the properties of release.

In other words, the presence of VAMP7 in a vesicle is an indicator of whether it’ll be released or not. This overturns the previous assumption that some vesicles get transmitted because – more or less – they’re in the right place at the right time. But now we know that vesicles don’t just get “discovered” like aspiring actresses – each one is born for its job, just as some of us are born to ride, run, or be wild.

As a paper published in the journal Neuron reports, a team led by UCSF’s Robert Edwards tagged various proteins with glowing (bioluminescent) molecules found in jellyfish. They found that VAMP7 levels are high in the resting pool of vesicles – the one that stays inside the neuron – but much lower in the recycling pool, which contains the vesicles that get transmitted, then recycled for later use.

Since the resting pool of vesicles can be 80 percent larger than the recycling pool, Edwards is sure it plays a significant purpose – but no one has any idea what that purpose is yet:

Resting vesicles are involved in a separate not-well-understood process in which neurons spontaneously release vesicles, which may help them adjust the types of connections they make with each other as well as the strength of those connections.

Since these vesicle differences may apply to all neurotransmitters in all neurons, it looks like we’ll need to correct some major misunderstandings about how the nervous system works. For one thing, we’ll probably need to reassess how we understand brain diseases whose symptoms stem from synaptic transmission problems.

It’s going to be really interesting to see what future research tells us about these resting vesicles, and what kinds of secret missions they get sent on when they’re not resting.


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