Astrocytic GABA and Circadian Timekeeping

Welcome to this episode of the Heliox Podcast! Ever wonder how your brain manages to keep time, waking you up without an alarm or syncing your daily rhythms? Today, we’re diving deep into cutting-edge research that flips the script on circadian biology.

Join us as we uncover the surprising role of astrocytes—those unsung heroes of the brain—and their production of GABA in orchestrating our internal clocks. This fascinating journey takes us through groundbreaking studies that challenge what we know about the brain’s master clock, the SCN, and explores how these discoveries could reshape our understanding of jet lag, sleep disturbances, and even conditions like Alzheimer’s.

Curious minds, let’s explore the hidden timekeepers at work in your brain!

A 'chemical metronome': Researchers uncover how astrocytes help the brain's master clock keep time
https://medicalxpress.com/news/2024-12-chemical-metronome-uncover-astrocytes-brain.html

More information: Natalie Ness et al, Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus, The EMBO Journal (2024). DOI: 10.1038/s44318-024-00324-w

Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus
https://www.embopress.org/doi/full/10.1038/s44318-024-00324-w

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Transcript

0:24

Ever wonder how your brain keeps time? You know, like how it just knows when to wake you up even without an alarm clock? Well, today we're going to unpack some seriously cool new research about that. That's right. We're diving deep into a study from the MBO Journal. Oh, and it was published just last week. Yeah, super recent. It's all about how our brains maintain those internal clocks of ours. The title is a bit of a mouthful, though. Yeah. Rhythmic Astrocytic GABA Production Synchronizes Neuronal Circadian Timekeeping in the Suprachiasmatic Nucleus. Catchy, right. But trust me, the research itself is way more exciting than that title. It really is. Basically, we're going to be talking about those underappreciated brain cells called astrocytes. You know, the ones everyone thinks are just kind of there. Yeah, exactly. But they actually play a pretty unexpected role in our circadian rhythms. Definitely more than we thought. But OK, before we get to the astrocytes, let's set the stage a little bit. We're talking about the Suprachiasmatic Nucleus. The SCN. Which is like basically the brain's master clock. Exactly. It's this tiny region in the hypothalamus, tiny but mighty. For sure. And it governs all sorts of circadian rhythms. Your sleep-wake cycle, hormone release, even those fluctuations in your body temperature. It's like the conductor of the body's orchestra or something. Keeps everything in sync. Perfect analogy. And you might have heard about clock genes. Oh yeah, like Per-2. Yeah, exactly. They cycle on and off throughout the day and they kind of help drive all these rhythms. But this research actually goes beyond just those genes. It really does. It looks at the way neurons and astrocytes communicate within the SCN. Right. And one of the key things they focused on in this study is this idea of a phase wave of neuronal activity in the SCN. Right. So what does that even mean? So imagine neurons firing in a specific pattern, like a wave, over several hours. And this synchronized wave-like activity. Well, it's thought to be super important for keeping that internal clock really precise. So it's not just individual neurons ticking away. It's like a coordinated effort. Exactly. That keeps the rhythm going precisely. Now, remember those astrocytes we were talking about earlier? Yeah, the underappreciated ones. Well, researchers have already shown that these astrocytes can actually drive circadian rhythms in mice. Seriously? Yeah. They even managed to restore rhythms in mice that were, get this, genetically arrhythmic. Wow, that's pretty amazing. It is. But in this study, they found something even more surprising. It turns out that astrocytes across the SCN, they exhibit this strikingly uniform activity. And it peaks at night, which is a stark contrast to that wave pattern we see with neurons. They have those distinct phases across the SCN. So hold on. While the neurons are doing their wave thing, the astrocytes are just pulsing in sync. Yeah, pretty much. Okay, so why would they be doing that? That's what puzzled the researchers too. And the answer, well, it might lie in a neurotransmitter called GABA. Oh, I've heard of GABA. Yeah, most people have. It's usually associated with, you know, calming down neuronal activity. A brain's chill pill. Exactly. Okay, so what does GABA have to do with keeping time then? Well, here's the mystery. Prior studies had shown that GABA levels in the SCN actually peak at night. Okay. But neuronal firing is highest during the day. Huh, that doesn't really make sense. Right. You'd expect GABA, you know, the one that inhibits neuronal activity, to be most abundant when the neurons are the most active. Yeah, you'd think. So the researchers decided to take a closer look. Makes sense. They simultaneously measured presynaptic calcium. Which is? Basically, it's a way to measure how active those neurons are. Oh. And at the same time, they measured the extracellular GABA levels. Got it. And guess what? They found them to be totally out of sync. Oh, no way. Yeah. GABA was peaking a full 13 hours after peak neuronal activity. Whoa, that's a long delay. So something else is going on. Right. It's more than just neurons releasing GABA in response to their own activity. Exactly. And here's another clue. That extracellular GABA, it was also uniformly distributed across the SCN. Huh, interesting. Unlike that neuronal wave pattern we talked about. Okay, so hold on. Remember how we were talking about that astrocytic activity? Yeah. How it was also uniform and it peaked at night? Yeah. I think I'm starting to see a connection here. I think you're right. Astrocytes, GABA, nighttime peaks, it's all coming together, isn't it? Yeah, but how did they actually prove that the astrocytes were the source of all this mysterious GABA? Well, they used a pretty clever trick to specifically block the release of GABA just from the neurons. They used a tetanus toxin that prevents synaptic vesicles from releasing their contents. So basically silence the neurons and see what happens to the GABA levels. Precisely. And the results, well, they were pretty fascinating. As we expected, blocking that neuronal GABA release caused the neuronal phase wave to get all desynchronized. Right. And the expression of that PR2 clock gene, it weakened too. Makes sense. Which suggests that the synaptic GABA from the neurons, it really is important for keeping those rhythms running smoothly. Okay, yeah, I buy that. But what about the GABA levels themselves? Did they, like, drop when neuronal release was blocked? And this is the kicker. The rhythm of extracellular GABA continued, totally unfazed by that neuronal blockade. Whoa, are you serious? Yeah. Which strongly suggests there is another source of GABA in the SCN. One that doesn't rely on those neuronal synapses. Okay, I'm on the edge of my seat. We've got synchronized astrocytes peaking at night, GABA levels also peaking at night, and neuronal GABA release isn't accounting for it. I think it's officially time to hand the mic over to the astrocytes. I think you're right. All signs are pointing to astrocytes as the secret GABA makers in this whole circadian story. So how are they doing it? Well, stay tuned, because in the next part of our deep dive, we'll unravel exactly how the astrocytes pull off this pretty unexpected feat. Thank you for being curious and subscribing, following, liking, rating, and reviewing our podcast episodes. Your support really helps build a vibrant Heliox community. Back to Heliox, where evidence meets empathy. Welcome back. Last time we left off with some pretty compelling evidence that astrocytes could be the secret source of those rhythmic GABA signals in the SCN. Yeah, those rhythmic signals. How do they actually make GABA? I mean, that's usually a neuron thing, right? Right. Neurons typically produce GABA using a specific pathway. Oh, yeah. It involves those enzymes called GAD65 and GAD67. But you're not going to find those enzymes in astrocytes. So how do they do it? How do astrocytes make GABA? Well, it turns out they have their own unique way of synthesizing it. It's called the polyamine degradation pathway. Polyamine what now? Yeah, it's a little, it's a bit more roundabout than how the neurons do it. Polyamines. Can we break that down a little? Sure. Polyamines are basically these organic compounds. They're involved in all sorts of cellular processes, you know, like cell growth and division. So like cellular building blocks. Yeah, exactly. And it turns out that astrocytes can actually break down a specific polyamine called putrescine to produce GABA. So they're repurposing these building blocks into signaling molecules. Pretty clever. It is. And to confirm this hunch, the researchers dug into some single cell RNA sequencing data, mouse brains. They wanted to see if the astrocytes in the hypothalamus actually express the genes that are needed for this non-canonical GABA pathway. Oh, that makes sense. The hypothalamus is where the SCN lives, of course. Right, right. So they were looking for the genes that code for the enzymes involved in that pathway. Exactly. They focused on two key enzymes, MAOB and ALDH1A1. Gotcha. They're like the workhorses of that whole polyamine to GABA conversion process. Right. And their analysis showed that these genes, well, they're definitely expressed in hypothalamic astrocytes. So the astrocytes have the instructions to make GABA, but are they actually, like, doing it in a rhythmic way? Like, does it match up with those nighttime GABA peaks? That was the next question, of course. Yeah. And while the RNA sequencing data gave them another clue, the expression of the ALDH1A1 gene... Which codes for? The ALDH1A1 enzyme. It was rhythmic, and it peaked during the night. When GABA levels are on the rise, okay, that's pretty convincing evidence right there. It is. They're not only making GABA, they're doing it in a way that's, like, relevant to the circadian clock. Right. But the scientists wanted to go beyond just correlation, you know? Of course. Yeah. They needed to directly test what would happen if they actually blocked that astrocytic GABA production. Okay, but how do you even do that? Stop astrocytes from making GABA without messing with the neurons? That sounds tricky. It was, but they figured it out. They used specific drugs to inhibit those key enzymes. The MAOB and ALDH1A1. Okay. Basically, they put the brakes on that whole astrocytic GABA production line. So cut off the GABA supply and see what happens to the SCN rhythm. Exactly. What'd they find? Well, the results were pretty striking. When they blocked MAOB, the first enzyme in that pathway, the circadian rhythm of extracellular GABA totally disappeared, just gone. Wow. Blocking ALDH1A1 had a milder effect. Okay. And temporary. Interesting. Which suggests that the pathway might have some backup mechanisms. Fascinating. So astrocytic GABA production is essential for maintaining those rhythmic GABA signals. It seems like it. Yeah. But how does that impact the neurons themselves? I mean, we know they're the ones driving that circadian rhythm with their activity and the clock gene expression. Right. And that's the really interesting part. Blocking either one of those enzymes actually caused neuronal calcium and PER2 expression to spike. And remember, GABA is inhibitory. So if you suddenly take away that inhibitory signal, well, it makes sense that the neuronal activity and the clock gene expression would increase. By taking your foot off the brake, right? Exactly. But the biggest finding, it came when they looked at the synchronization of the SCN. Remember that precisely timed phase wave of neuronal activity? Oh, yeah. When they blocked astrocytic GABA production, it caused both the neuronal activity and the clock gene expression to desynchronize across the whole SCN. Whoa. So astrocytic GABA isn't just contributing to overall GABA levels. Nope. It's like conducting, keeping the whole SCN orchestra in sync. That's the key takeaway. They were so impressed by this finding, they even came up with a new term for it. Oh, what's that? Astrozyte. Astrozyte. That's pretty cool. Right. It really captures what they found. Yeah, it does. But what does it all mean for, like, you and me? Why should we care about this astrocytic GABA and its whole timekeeping role? What are the implications? Those are great questions, and we're going to explore those in the final part of our deep dive. We'll look at how this research could help us understand things like jet lag and maybe even shed light on diseases like Alzheimer's. Hey there, listeners. If you're enjoying today's episode, check out our previous episodes where we dive deep into fascinating topics in scientific research and more. Don't forget to tell your friends and family about Heliox. Back to Heliox, where evidence meets empathy. Welcome back to the show. So we've been on this journey, you know, unpacking this whole astrocytic GABA mystery. It's been quite the ride. It has. And now it's time for the big question. So what? Right. Why should we even care about these timekeeping astrocytes? Well, that's what I love about science. It forces us to rethink everything we thought we knew. This research really does flip the script on how we understand the circadian rhythms. I mean, it's not just about neurons and clock genes anymore. Right. There's this whole other layer of complexity with astrocytes playing, you know, a crucial role. And it has implications for, like, all sorts of things, right? Yeah. Absolutely. You mentioned jet lag and Alzheimer's disease. Yeah. So let's start with jet lag. I mean, we've all felt it, right? That grogginess? Oh, yeah. When our internal clocks are just out of whack with our environment. Ugh, the worst. Could these astrocytic GABA signals actually be part of the solution? The study authors seem to think so. They suggest that astrocytic GABA kind of acts like a backup system, like a stabilizing force when our neurons are trying to adjust to a new time zone. So like a steady hand on the wheel while our neuronal GPS is trying to, you know, recalibrate. Yeah, exactly. You fly across several time zones, your neurons are hit with all these, like, conflicting light-dark cues. Right. And they're trying to figure out what time it is. Makes sense. Meanwhile, the astrocytes just keep chugging along. Right. Releasing GABA in their, you know, steady, rhythmic way, helping to keep things somewhat on track. Okay. Until the neurons can catch up. That could explain why we eventually adapt to those time shifts. Even if it takes a few days of feeling completely out of it. Yeah, exactly. So astrocytes, the rescue for jet lag. All right. What about Alzheimer's? That's a bit more concerning, you know? Yeah, it is. And it shows just how important this astrocytic GABA signaling really might be. Researchers have seen this disrupted GABA signaling in the SCN in the early stages of Alzheimer's disease. And we know that Alzheimer's is also characterized by reactive astrocytes. Reactive? Astrocytes that have become dysfunctional, basically. So we've got dysfunctional astrocytes, messed up GABA signaling, and Alzheimer's. I see where you're going with this. Yeah. The study suggests that this disruption in astrocytic GABA could actually be contributing to those sleep disturbances that are so common in Alzheimer's patients. Makes sense. You know, if the SCN isn't working properly, the whole circadian rhythm can get thrown off. Yeah. And that can lead to all sorts of problems. That's pretty unsettling. But it's also, like, potentially a new avenue for treatment, right? Could be, yeah. If we can figure out how the astrocytes go wrong in Alzheimer's, maybe we can find a way to target them. Yeah. And improve those sleep problems. Absolutely. It's early days, of course. Sure. But this research opens up some really exciting possibilities for understanding and, you know, potentially treating a whole range of neurological conditions. It really is amazing to think about, you know? Yeah. Something as simple as our sleep-wake cycle is actually governed by this crazy, complex interplay between neurons and astrocytes. It is, yeah. We've gone from clock genes to this whole network of cellular communication. And it turns out, even those underappreciated astrocytes are playing a key role. They're finally getting the spotlight. They are. I don't know about you, but after all this, I'm definitely giving my astrocytes a lot more respect. Me too. They're clearly more important than we ever imagined. Well, dear listeners, we'll leave you to ponder the wonders of astrocytic timekeeping. Maybe next time you're struggling with jet lag or, you know, marveling at your brain's ability to wake you up at the right time, you'll spare a thought for those amazing astrocytes working tirelessly behind the scenes to keep your internal clock ticking. Until next time, happy deep diving.