Epilepsy: The Brain-Mind Connection - Leszek Kaczmarek, Nencki Institute of Experimental Biology, Poland
Neurobiologist Leszek Kaczmarek chats about his extensive research into the role of the MMP-9 protein in learning, memory, and epilepsy! We hear about its link to synaptic plasticity, epilepsy, autism, and various mental health disorders - like depression, schizophrenia, and alcohol addiction! Transcription and links to Leszek, below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
-
00:00 Leszek Kaczmarek
So, we used seizures, originally, as a way to understand what we are doing. Because the protein we discovered, its name is c‑Fos is a regulator of other genes. So, we kind of discovered a conductor in the orchestra.
00:16 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and, welcome to, or welcome back to: Epilepsy Sparks Insights. If you’re new/haven’t done so already, please do like and comment on this episode and subscribe to our channel - so to support our mission to decrease the discrimination faced by and improve the quality of life of those affected by the epilepsies…. Aaaaand get everyone appreciating - and encouraging funding for the amazing epilepsy researchers out there!
Now, many of us know that there are close correlations/links between loads of diseases - including the epilepsies, mental health disorders (including psychosis and schizophrenia - which aren’t spoken of enough - in my opinion!)), intellectual disability, cognitive disfunction, and way more. So, that’s why it’s incredibly cool that I can today, introduce you to, the fabulous neurobiologist and research lead/PI Lezek Kaczmarek!
01:07 Leszek Kaczmarek
I work at the Biological Institute in Warsaw, Poland. It's called Nencki. I established a group in 1986 working on molecular neurobiology, trying to address questions of relationships between brain and mind, starting from learning and memory in animal models.
01:28 Torie Robinson
Can you tell us how this relates to the epilepsies, please?
01:32 Leszek Kaczmarek
It is rooted in this learning and memory studies because what we discovered ([in] late 86) was that when rats learn new things, there can be induction of a gene expression in the brain. But originally, the first experiment was actually not even learning that the rats learn something what is good, what is bad, but we injected into the brain a substance, a neurotransmitter, that is critical for establishing changes in neural circuitry that underline learning - and this is called glutamate. And then we wanted, again, to follow this, and putting something into the brain is complicated… you drill a hole into the skull and so on - that's not easy and nice.
So, our colleagues from Kraków, they showed us there's another way that you can inject the animals with an analog of the glutamate (it is called kainate). That you can inject intraperitoneally ([which] means peripherally, not to the brain). The drug penetrates to the brain, activates neurons…but it activates neurons, the the glutamate has to act on so-called receptors, so it activates glutamate receptors, neurons get activated, spiking activity (electrical activity), and they release their own glutamate to activate other neurons. So, it kind of perpetuates and results in seizures episodes.
So, we used seizures, originally, as a way to understand what we are doing. Because the protein we discovered, its name is c‑Fos is a regulator of other genes. So, we kind of discovered a conductor in the orchestra, in the neurons, the genomic (we say) response. So, we wanted to see what are the genes regulated by this transcription regulator. And then we found a gene and documented that it's regulated by this c‑Fos And the gene encoded a protein called TIMP-1 (Tissue Inhibitor of Matrix Metalloproteinases).
Then we ask, "Okay, what is TIMP-1 doing? We never heard about that before.". Okay, and it turned out that it's a protein that inhibits activity of some other proteins outside the cells (extracellularly), especially MMPs (Matrix Metalloproteinases), and among them MMP-9 (because there's over 20 and each of them has a number). So, we follow with this MMP-9. And since we started with seizures and then we followed this MMP-9 it's also strongly activated by seizures. Okay? We just ask "Okay, seizures, especially status epilepticus, (intense seizure episode), may lead to epilepsy through epileptogenesis, the process, [the] latent process of developing epilepsy. So, let's see whether our MMP-9 contributes to the epilepsy. So, this was a paper published a long time ago (in 2008), in which the most important finding was that we used mice that were missing a gene encoding this MMP-9. This is called a knockout. There are over 20,000 genes in humans and mice and only one through genetic manipulation was missing. And we showed that those mice are somewhat protected from developing epilepsy! So, then we produced transgenic rats, rats that have additional copies of a gene and coding MMP-9, but only in neurons, selectively in neurons. And [it] turned out that those guys are more prone to develop epilepsy. So at that time we provided evidence that MMP-9 contributes to epilepsy.
And, on the side, we still continued learning and memory experiments, etc., and actually showed that this MMP-9 contributes to learning and memory as well. So, in that sense, the link is a protein that is important. And there's a very simple explanation which we have also provided "Why is that?". Because learning and memory is this producing adequate responses (our responses, animal responses), to incoming stimuli from the environment.
If we see that if the stimuli we met before, we were exposed to before, or [which was] similar [to that of which] we were exposed to before. And this exposure to the new stimulus for the first time somewhat reorganises [the] neuronal network that forms the brain. And this reorganisation is called plasticity. By the way, this is the term introduced. It's very widely used. Not very many people know. The car (sic), actually, was introduced by Jerzy Konorski from the Nencki Institute in Warsaw in 1940.
06:40 Torie Robinson
I didn't know that, okay!
06:41 Leszek Kaczmarek
I have to follow the giant and stand on the shoulders of the giant!
So, anyway, so, we implicated this MMP-9 in the plasticity. And what means plasticity? Plasticity means that the neurons are more or less responsive to other neurons inside the brain. And this happens: neurons are connected through synapses. These connections are called synapses. And the synapses may be of different shape and size. And what we found is that MMP-9 contributes to the modification of this shape and size of synapses. The excitatory so-called synapses. Those synapses that respond to glutamate, are located ([the] vast majority of them), on the small protrusions on the membrane of neurons on the part called dendrites. So they are called dendritic spines, like spines or rocks. And then we found that MMP-9 is critical for [the] reorganisation of dendritic spines. And epilepsy is also a disease that may have roots in this abnormality of synaptic plasticity. So, there's a physiological synaptic plasticity leading to learning and memory, but maybe pathological synaptic plasticity that may lead also to epilepsy.
08:01 Torie Robnison
Fascinating. And so, tell us a bit more about the links between the epilepsies and mental health disorders. I've read that you've written about schizophrenia and autism and cognitive dysfunction. What are the links between those things in your work?
08:20 Leszek Kaczmarek
In our work: MMP-9. Because, sometimes those diseases are called synaptopathies. It means pathology of synapses. And we showed that MMP-9 is critical for the proper functioning - or maybe when abnormal, to dysfunctioning - of those synapses. So, in that sense, we have implicated MMP-9 in alcohol addiction, in depression, in autism spectrum disorder, as well as schizophrenia. We study mostly animal models or even in vitro cultures of neurons very distant from the brain, may say. But we collaborate with clinicians. And the studies have been really validated on the cohorts of patients because the nature made an experiment on us. And this experiment is that the gene for MMP-9 comes in various so-called polymorphic variants. There are not mutations, but small changes in the structure of a gene. And somewhat these changes may result in different levels of MMP-9 production, including at the synapse. So, clinicians study patients, study the polymorphism, and then we link the polymorphism, "this" variant versus "this" variant, to "this" and "this" symptoms of disease. For example, we found that MMP-9 with 09:50 Hannel or Escher and Reich from Göttingen, we found that MMP-9 contributes to hallucinations in schizophrenia or with Jerzy Samochowiec from Szczecin: to greater motivation or lower motivation to seek alcohol in alcoholics.
10:03 Torie Robinson
It is amazing really. And this is just one sort of protein, right, that has this impact that we know of.
10:10 Leszek Kaczmarek
What I'm saying here is that, okay, we have over 20,000 genes. Genes may code even for more than single proteins. So, we have tens of thousands of proteins, but in a way, it's how they build the cells. They make cells to be reactive to something; there are structural, there are enzymes, they are functional in various ways. But I would say that there some are permissive to whatever activity cell performs and some are instructive. Those are the rulers of the game! And MMP-9 is one of those instructive proteins. So, this is, I think it's more important than others, but obviously I'm biased because I study MMP-9!
10:51 Torie Robinson
Okay. Have you discovered anything that has surprised you or contradicted your presumptions about this gene or about the effects of this gene or what [are] the causes of these diseases [are]?
11:02 Leszek Kaczmarek
I'm not sure really. It means that we are, okay, my research, say neuroscience research started in 1986 and it sort of follows kind of, results. We ask a question and then we follow the results. So we are open to whatever comes! We don't make too many predictions like this. We ask specific questions. Does it contribute to epilepsy? Or, does not. So, we may hypothesise that it does, but okay, it does. So, it's not really very surprising. There are minor technical things that might be surprising, which is the time course of the activity and so on. This is a protein, so this is the enzyme. This is a protein that digests, cleaves other proteins. So, understanding what are the targets, this was kind of a surprise, etc., etc.. But fundamentally, I think I'm kind of happy that what I started in 1986 is ongoing work.
12:03 Torie Robinson
That is science. I love it. I love it. What do you foresee the next 5 to 10 years holding for your research and the potential impact maybe on people affected by the epilepsies? I understand that, you know, you've already said that you are working with rodents and in vitro, but do you, what do you think the future may hold?
12:22 Leszek Kaczmarek
I am curiosity driven. When I was young boy and was given a watch, my first thing was [to] disentangle this watch! And I tried to put it together, some parts remained, sometimes it worked, sometimes it didn't! So, I'm still like that. So, I want to know how things are. So, it's very fundamental in a way. But, when I see potential for translation application, I do not escape because it is also interesting trying to do this. So, with this MMP-9: the MMP-9 is an enzyme. Enzymes can be blocked by things called inhibitors. So, enzymes can be inhibited. And there are many drugs that are inhibitors of enzymes. And actually over 20, 30 years ago, MMPs, including MMP-9, were targeted by potential therapies, by drugs that were inhibitors of these enzymes, because we've proven that MMPs contribute to cancer metastasis. And this has been shown very well in animals, in this in vitro culture, and then they went to human clinical studies, even so-called phase 3 clinical studies, big studies. And everything failed. Billions and billions of whatever Dollars, Pounds, Euros were lost because people suffered from the pain (musculoskeletal pain), because to prevent metastasis they were given the drug chronically for long time. So, what we discovered, [is] that this MMP-9 is activated by those conditions provoking epilepsy, so-called "acutely", within minutes to hours! Within a couple of days, MMP-9 is entirely gone! The plasticity, this reorganisation happened and may produce long-lasting effects, but MMP-9 doesn't play a role. It's not involved in maintaining the effect. It just produces the effect.
14:28 Torie Robinson
Mmm, just like a trigger, right?
14:30 Leszek Kaczmarek
It is a trigger but it's not involved in maintaining this/making it sustainable. So what happens is, I had this idea (I published this over 10 years ago), so maybe we should reconsider, it is called repurposing those drugs to some neuropsychiatric disorders in which MMP-9 is triggered for a short time. And epilepsy is a prime example. And the conditions in adults to develop epilepsy are mostly, most often like traumatic brain injury, because car accident, exercise accident, or war thing and so on, or stroke.
Leszek Kaczmarek
15 to 20 [percent of] people after traumatic brain injury or stroke suffer from epilepsy that develops over, like, even a couple of years. And this process is called epileptogenesis development from stroke. So, we hypothesise, maybe some of those drugs can be repurposed to prevent epileptogenesis or at least slow [it] down and so on. And what happened… so we had a project with colleagues with the company: okay, let's take over 10 of those drugs and see whether they penetrate to the brain. Because brain is protected by so-called blood brain barrier; it's not easy for the molecules to penetrate. And we discovered a couple that do penetrate. So then we tested whether they sort of slow down, prevent (partially, at least), a development of epilepsy in mice. And we found a drug that worked quite well. It's called Marimastat. So we went…then I teamed up with a small company established in Poland, (the name is Pikralida) and they decided to follow this. So, we applied for patents worldwide, we sold them licenses to follow, then we got a joint grant project with them, and we still continue to collaborate. And they had to make a formulation of a drug that would be suitable to humans, and they, they went all the way to so-called phase 1 clinical trials. It means whether the drug is safe in humans. It proved to be safe in much higher doses that are needed to prevent development of epilepsy in animals. So what they are interested [in] now? They are interested in, they have to find funds to go to clinical phase 2 trials to see the efficacy. So, it is all the way still in progress, and hopefully, if you ask [me in] 10 years: why not, [there] could be a drug that would prevent [the] development of epilepsy.
17:11 Torie Robinson
Thank you so much to Lezek - for giving us what was, really, a rather scientifically, academically enticing insight into his brain-mind research (because I don’t know about you - but I already want to know more!). Check out more about Leszek and his research on the website t o r i e robinson.com (where you can also access the podcast, the video, and the transcription of this episode) all in one place, and…
If you haven’t already, don’t forget to like, comment, and subscribe to the channel, and share this episode with your friends/colleagues/family members/universities, and schools - whoever…the whole shebang(!) - because this supports our mission to decrease the discrimination faced by and improve the quality of life of those affected by the epilepsies… aaaaand get everyone appreciating - and encouraging funding for the incredibly cool epilepsy research out there!
See you next week!
-
Leszek Kaczmarek is professor of neurobiology at the Nencki Institute, Warsaw, Poland. He carried out postdoctoral studies in Philadelphia, USA and then was a visiting professor at the University of Catania, Italy, at McGill University in Montreal, Canada, at the University of California in Los Angeles, USA, and at the Institute of Photonic Sciences, ICFO, Castelldefels, Spain. Since 1986, his lab has been investigating brain-mind connection at all levels of brain organisation in health and disease - from molecular to cellular to network to behaviour! Although most of his work involves experimental animal models, joint studies with clinicians on human neuropsychiatric disorders have also been pursued. Leszek’s current major focus is on extracellular enzyme, matrix metalloproteinase, MMP-9, which his lab documented to play a paramount role in neuronal/synaptic plasticity and then in learning and memory, the development of epilepsy, schizophrenia, autism spectrum disorders and alcohol addiction.
Leszek is very active in professional scientific organisations, serving on the governing bodies of the International Society for Neurochemistry, the International Brain Research Organization, the European Molecular Biology Organization, the European Molecular Biology Conference (currently as the president), the National Science Center (Polish research grant agency), the Polish Academy of Sciences, and the Polish-US Fulbright Commission. At the European Research Council, he served 7 times in evaluation panels, recently chairing the LS5 Neuroscience and Neural Disorders Consolidator grant panel. He has been engaged in multiple outreaching activities promoting science into society and he co-authored a biology textbook at middle school level.
Leszek is a member of the Polish Academy of Sciences, the European Molecular Biology Organization, and Academia Europaea. He has been awarded several prestigious research grants and recognitions including the Foundation for Polish Science (FNP) award for his research on inducible gene expression in the brain. The FNP award is the highest recognition in Polish science. He is currently Full Professor at the Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
-
European Research Council leszek-kaczmarek
Nencki Institute of Experimental Biology kaczmarek-leszek
EMBO leszek-kaczmarek-becomes-new-embc-president
ResearchGate Leszek-Kaczmarek-2