Brain Science with Ginger Campbell, MD

Episode 211: Molecular Biologist Seth Grant—How Synaptic Protein Lifespans May Shape Memory, Brain Health, and Disease
Release Date: August 25, 2023
Guest: Dr. Seth Grant, Professor, Molecular Neuroscience, University of Edinburgh
Host: Dr. Ginger Campbell

Episode Overview

In this episode, Dr. Ginger Campbell welcomes back Dr. Seth Grant for a record sixth interview, to discuss his lab’s landmark research mapping the lifespan of synapse proteins across the mouse brain. Dr. Grant, a pioneer in applying molecular biology to neuroscience, explains how measuring the longevity of scaffold proteins like PSD-95 can yield critical insights about memory formation, brain aging, resilience to disease, and the striking molecular complexity that makes vertebrate brains special.

Key Discussion Points & Insights

The Molecular Biology Revolution in Neuroscience

• [03:45] Dr. Seth Grant recounts entering the field when gene manipulation in mice was just emerging, having previously worked on oncogenes and cancer genes at Cold Spring Harbor Laboratory.
• The introduction of molecular biology allowed dramatic advances: "For the first time, you could put a gene into a mouse and see what it did… This was a tremendous transition… the field had been dominated by electrophysiology and anatomy and pharmacology." (05:38)
• This led to the birth of the "knockout mouse" as a research tool—pioneering experiments published alongside Susumu Tonegawa’s MIT lab in 1992.

The Importance & Surprise of Synaptic Diversity

• In the early 1990s, scientists only knew of a literal handful of proteins in synapses; today, mass spectrometry reveals thousands. (08:11–09:30)
• PSD-95, a "scaffold" protein, acts as a molecular hub—"a very versatile sort of Swiss army knife kind of molecule." (11:29)
• Genome duplications 500 million years ago expanded these proteins in vertebrates, greatly increasing synaptic complexity, which Dr. Grant’s work shows is linked to behavioral sophistication. "That's one of the reasons we're so very clever." (14:38)

Dr. Grant’s Featured Research: The Lifespan of Synaptic Proteins

• At the core is their new study, "A Brain Atlas of Synapse Protein Lifetime across the Mouse Lifespan" (Neuron, 2022), which is freely available via PubMed. (18:47)
• The key question: How long do synaptic proteins like PSD-95 actually “live” inside synapses? Until now, estimates were based on brain averages—not at the single-synapse level.

Crick’s 1984 Paradox

• Francis Crick raised a compelling question: “How can memories last a lifetime if synaptic proteins are constantly being replaced?” (27:09)
• Although proteins in the brain generally turn over in days to weeks, Dr. Grant’s new technique allows tracking how long specific synaptic proteins persist at the single-synapse level.

Methodological Breakthrough: The HaloTag Mouse

• Grant’s team tagged the PSD-95 protein in mice with a “halo tag,” allowing them to use a fluorescent ligand that irreversibly labels the protein when injected.
• "It forms a covalent bond... you inject the mouse and suddenly boom, all the synapses light up." (32:41)
• By imaging the same brain regions over weeks to months, they could determine how long the labeled proteins remained in specific synapses across the mouse brain.

Major Findings

1. Rapid vs. Long-lived Synapses

• [33:30–38:19]

• Most synapses rapidly replace their PSD-95 protein in as little as two weeks.

  “It's as though you took a city like Manhattan… and said, ‘I'm just going to rebuild the thing every three months,’… just replace every brick and every girder… that's what the brain's doing.” (33:44 – Dr. Grant)

• Exception: In certain areas—most notably the latest-evolved, superficial cortex and parts of the hippocampus—some synapses retained their PSD-95 for months or longer.
• These areas are associated with long-term memory storage.
• Conversely, “the proteins with the shortest protein lifetime... are heavily enriched and populated in those parts of the brain [that] control innate behaviors”—the ancient brainstem and hypothalamus. (36:43 – Dr. Grant)

2. Functional Implications: Memory, Stability, & Aging

• [40:26–44:59]

• The diversity of synapse protein lifespans adds a new dimension to “synaptome architecture.”
• Synapses with rapid turnover might enable flexibility and constant updating (i.e., for learning new things or adapting to new environments).
• Synapses with slow turnover may underlie the stability needed for long-term memory and resilience to aging.

  "In an old animal, you have very slow protein turnovers and lots of these long protein lifetime synapses." (41:28 – Dr. Grant)

• Synapses most resistant to age-related loss are those with the longest protein lifetimes; those that disappear most with age are the rapidly turning-over type.

3. Tradeoffs & Disease Connections

• [47:47–50:03]

• Tradeoff: Long-lived synaptic proteins may accumulate damage or toxic aggregates (as seen in neurodegenerative diseases), while fast turnover synapses clear "garbage" more efficiently.

  “The long protein lifetimes keep the garbage in the house. Now, that could be a problem…” (48:13 – Dr. Grant)

• Implications for Schizophrenia & Autism:
  Mutations in synaptic genes (e.g., PSD-95's relative, PSD-93) alter synapse protein lifetime, with profound impact on cognitive flexibility and possibly leading to symptoms such as those seen in schizophrenia or autism.

  “What we found was that [schizophrenia-associated] mutation had really quite a profound effect on the lifetime of the PSD95 molecule… these mice… have impairments in their cognitive flexibility.” (51:54 – Dr. Grant)

Notable Quotes & Memorable Moments

• The Manhattan Metaphor:
  “The brain basically rebuilds that map in the mouse every couple of weeks. It's as though you took a city like Manhattan... I'll just replace every brick and girder... That's what the brain's doing...”
  (33:44 – Dr. Grant)

• Why focus on synapses and molecules?
  “You don't need a big, fancy wired up nervous system to do some pretty sophisticated stuff. It's the molecules that matter.”
  (62:09 – Dr. Grant, on the computational power of molecules in primitive and complex brains)

• On Scientific Discovery:
  “The hard thing when you're a very young scientist is to know what's important to work on… It's easy to answer any old question once you get going… the question's the hard bit.”
  (63:01 – Dr. Grant on advice for students)

• On the Purpose of the Brain
  “The genome built the brain for the genome. That's what it's for. It's not there for us to play chess or watch TV… It's there to protect the genome.”
  (67:07 – Dr. Grant)

Important Timestamps

| Segment | Timestamp | |--------------------------------------------------|-----------------| | Why molecular biology revolutionized neuroscience | 03:45–07:19 | | The expansion and origin of PSD-95 and DLG genes | 12:32–15:29 | | Mouse/human synaptic genetic conservation | 16:46–18:47 | | Evolution of synaptic diversity (synaptome) | 19:54–24:06 | | Crick’s “paradox” and synaptic memory | 24:06–30:54 | | The Halo-tag method | 30:54–33:30 | | Key findings: Synapse protein lifespans | 33:30–38:19 | | Implications for brain aging | 44:59–47:47 | | Tradeoff: Memory stability vs. toxic buildup | 47:47–50:03 | | Synaptic disease genes and psychiatric disorders | 50:03–53:36 | | The Human Brain Synaptome Project | 53:53–56:20 | | Fundamental “general principles” of brain science | 56:20–58:52 | | Synaptic machinery in evolution and octopus note | 58:52–62:37 | | Advice to young scientists and field funding | 62:37–66:50 |

What’s Next? Dr. Grant’s Vision

• Mapping the “Human Synaptome” to aid understanding of uniquely human capacities—especially as related to regionalization (like language and higher reasoning) in the cortex. His group is developing high-throughput imaging and quantification of synapse types in human postmortem brain tissue.
• Encouraging other labs to apply this new technique to measure lifespans of other synapse proteins (e.g., for dopamine or inhibitory synapses), and in other disease models.
• Big, open questions:
  • What makes certain synapses resilient to age—and others vulnerable?
  • How do toxic proteins differentially impact diverse synapse types?
  • How many fundamental "molecular principles" underlie behavioral complexity and disease?

Takeaways for Listeners

• The brain is not a static machine—it is constantly renewed at the molecular level, with intricate patterns of longevity that help explain both memory and vulnerability to disease.
• Synaptic protein lifespans are a newly appreciated dimension of brain structure and function, potentially key to everything from forgetting your keys to the onset of Alzheimer's.
• The diversity and architecture of synapses arise from hundreds of millions of years of evolutionary tinkering, giving us animal brains of astonishing subtlety—and new medical frontiers.
• As Dr. Grant so evocatively puts it: "If you really want to understand what's going on in the brain, you will never understand it unless you understand the genome and the importance of genome evolution." (67:44)

Memorable Final Recommendations

• “I'm a huge believer in the importance of basic fundamental science... If you said, ‘I'm going to try to treat schizophrenia, but I'm never going to bother working out what's in a synapse...’ We wouldn't know what schizophrenia was today.” (65:05 – Dr. Grant)
• Students: Seek good mentors, focus on the right questions, and “keep doing that. And I'm a huge believer in the importance of basic fundamental science.” (65:14–65:49)
• "The opportunities for research in this area are only limited by imagination and the stodgy habits of those who control funding." (69:19 – Dr. Campbell)

For further info, show notes, and full transcript: brainsciencepodcast.com