Episode 163: Mark Mattson discusses glutamate, the brain’s most important neurotransmitter
STEM-Talk
Understanding Aging Brain and Seizures
The incidence of seizures is higher in older people due to changes in the aging brain. Aging leads to increased hyper-excitability of neurons and a decline in GABAergic inhibitory neurons, which are crucial in constraining glutamatergic neurons and preventing seizures. The decline in the function of GABAergic neurons with aging and in conditions like Alzheimer's may lead to hyper-excitability and increased susceptibility to seizures. Activating GABA receptors with drugs could potentially help mitigate the effects of aging or Alzheimer's.
Today we have Dr. Mark Mattson, an adjunct professor of neuroscience at Johns Hopkins School of Medicine who is making his third appearance on STEM-Talk.
Today’s interview focuses on Mark’s research into glutamate and comes on the heels of the publication of Mark’s new book, “Sculptor and Destroyer: Tales of Glutamate – The Brain’s Most Important Neurotransmitter.”
Today Mark explains how more than 90 percent of the neurons in the brain deploy the little-known molecule glutamate as their neurotransmitter. Glutamate controls the structure and function of the brain’s neuronal networks and mediates many of our human capabilities, such as learning, memory, creativity, and imagination.
But there’s also a dark side to glutamate. Mark shares how it can play a causal role in the development of disorders such as autism, schizophrenia, and epilepsy as well as diseases such as Alzheimer’s, Parkinson’s, and ALS.
Mark is affectionally known as the godfather of intermittent fasting and his first appearance on STEM-Talk focused on the many ways that fasting optimizes healthspan and even lifespan. His second STEM-Talk interview followed the publication of his book, “The Intermittent Fasting Revolution: The Science of Optimizing Health and Enhancing Performance.”
Show Notes:
[00:04:05] Dawn welcomes Mark back to STEM-Talk for his third appearance. Dawn mentions that our previous two episodes with mark focused on intermittent fasting, and that Mark is considered the godfather of intermittent fasting. Dawn goes on to mention that the National Institutes of Health has described Mark as “one of the world’s top experts on the potential cognitive and physical health benefits of intermittent fasting.”
[00:05:05] Ken mentions that in our previous STEM-TALK interview Mark shared that he was working on a new book about glutamate. Ken adds that Mark considers his research on glutamate to be his most important work. Ken asks why Mark feels as though this research is his most important, given his substantial contributions in other areas.
[00:05:49] Dawn mentions that Mark’s research hasn’t been limited to just glutamate and intermittent fasting. Mark has contributed to a broad range of topics including brain evolution, cognition, the impact of diet and lifestyle on brain health, as well as the pathogenesis and treatment of various neurological conditions. Dawn asks Mark to talk about his motivation to understand how the pieces of the “brain puzzle” fit together, which is the core motivation for his pursuing a broad scope of research.
[00:07:22] Ken asks about Mark’s postdoc work, where he discovered that glutamate sculpts the formation of hippocampal neuronal networks during development.
[00:09:33] Ken mentions that while Mark was at the University of Kentucky, he discovered that the amyloid beta peptide which accumulates in the brain during Alzheimer’s disease renders neurons vulnerable to excitotoxicity. Ken goes on to say that since this, and the previously mentioned discovery, neurologists have shown that neuronal network hyperexcitability occurs early in Alzheimer’s and may contribute to neuronal degeneration. Ken asks Mark to talk about the significance of these two discoveries.
[00:13:39] Dawn asks Mark to talk about the significance of glutamate as a molecule and how it controls the formation of nerve cell networks as the brain develops in utero.
[00:17:50] Ken asks Mark why he thinks that glutamate rarely comes up in discussions of neurotransmitters, despite its importance of its functions.
[00:19:58] Ken asks Mark to expound on the “dark side” of glutamate.
[00:26:04] Dawn mentions that we may never know where in the universe glutamate originated, and while it might have been here on Earth, it perhaps originated somewhere else in the universe. Dawn asks Mark to expand on that notion.
[00:28:33] Ken shifts to the history of glutamate research, explaining that up until the 1940’s, researchers largely ignored the possibility that glutamate was a neurotransmitter. But then a Japanese professor during WWII demonstrated that glutamate could excite neurons. Ken asks Mark to discuss the significance of this finding.
[00:31:44] Ken explains that the brain, while only comprising two percent of body weight, utilizes 20 percent of the body’s energy output, roughly 400 calories in a 24-hour period. Ken asks Mark to explain the role that glutamate plays in the utilization of energy in the brain.
[00:33:32] Dawn mentions that in the first half of Mark’s book, he explains how glutamate controls the structure of neuronal networks in the brain, and how it plays a role in not only mediating the brain’s ability to learn and memorize, but also contributes to inspiring creativity and imagination. Dawn asks Mark to discuss the essential role that glutamate plays in our lives.
[00:41:04] Dawn mentions that the later chapters of Mark’s book delve into the “dark side” of glutamate, and how subtle aberrancies in the activity of neurons that deploy glutamate can result in behavioral disorders like autism, schizophrenia, chronic anxiety and depression. With the primary focus of this section of the book being how glutamate can overly excite neurons to the point of leading to a wide range of disorders like epilepsy, Alzheimer’s, Parkinson’s, ALS and even Huntington’s. Dawn asks Mark to explain how aberrant glutamatergic neurotransmission is a fundamental feature of so many different neurological disorders.
[00:47:22] Ken asks what the role of aging is in making neurons more vulnerable to excitotoxicity over time.
[00:51:07] Ken asks about the relationship between brain aging and glutamate.
[00:52:16] Ken asks Mark about a 2018 paper he wrote which discussed how the incidence of seizures is higher in older adults than in middle-aged adults. Ken asks Mark to explain how some of the features of the aging brain can stimulate the development of seizures.
[00:55:39] Ken mentions that at IHMC, we work with military populations that have suffered traumatic brain injury. Ken asks Mark to explain how glutamate leaks out following a TBI and the effects that has.
[00:57:26] Dawn mentions the chapter in Mark’s book titled “Eve of Destruction,” which explores the role of glutamate in Alzheimer’s, Parkinson’s and other neurodegenerative conditions. Dawn goes on to mention that on3 in every three people over the age of 65 will die with Alzheimer’s, and asks Mark to describe the symptoms of this disease and how it leads to the inexorable decline in the ability to remember experiences.
[01:03:52] Ken mentions that Mark has been quoted as saying that everyone is at risk for Alzheimer’s disease, not just certain populations, and asks why that is.
[01:07:15] Ken asks Mark to give a high-level overview of the research that suggests that ketone esters may benefit people at risk of cognitive impairment and Alzheimer’s.
[01:12:33] Dawn praises Mark’s new book, as well as his work on glutamate over the years. He asks Mark how he feels now that the book is published.
[01:14:21] Ken asks Mark how his recovery from his bicycle accident is going and if he has returned to cycling.
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