Brain Science with Ginger Campbell, MD: Episode 150 – Dr. Seth Grant and the First Mouse Synaptome Map

Podcast: Brain Science with Ginger Campbell, MD
Episode: 150 (Premium Ad-free)
Date: October 26, 2018
Guest: Dr. Seth Grant, University of Edinburgh

Episode Overview

This episode of Brain Science features a return visit from Dr. Seth Grant, a researcher renowned for his pioneering work on the molecular complexity and diversity of synapses. Dr. Grant and Dr. Ginger Campbell discuss his team's groundbreaking creation of the first comprehensive “synaptome” map of the mouse brain—a project that reveals astonishing diversity in synaptic architecture and suggests new ways of thinking about brain computation and memory.

Dr. Grant explains how synapse diversity and molecular mapping challenge traditional neuroscience models and could fundamentally change our understanding of cognition, memory, and mental disorders.

Key Discussion Points & Insights

1. Background to the Synaptome Project

• Genes to Cognition Program

  • Initiated in the early 2000s to bridge the gap between gene function and behavior.
  • Explores how genes and synaptic proteins regulate cognitive functions (learning, memory).

• Focus on Synapses

  • Historically viewed as simple connectors between neurons.
  • Current understanding: synapses are complex molecular computers that process information.

"The synapse... is not just a simple connector. Those proteins are doing far more than just serve the simple job of being a connector. What those proteins are doing is processing information."
—Dr. Seth Grant (05:06)

2. Traditional Models vs. Emerging Views of the Synapse

• Traditional Model: Each behavior equals a specific neural circuit; synapses are considered largely homogenous.
• Grant’s Model: There is vast synaptic diversity—potentially no two synapses are identical.
• Implication: Unique synaptic “molecular signatures” may underlie different behaviors and cognitive processes.

"The traditional model has been basically, all the synapses are more or less the same... we have found evidence that, in fact, there may be a very huge number of different types of synapse—great synapse diversity."
—Dr. Seth Grant (09:50)

3. Mapping the Mouse Synaptome

• Project Approach

  • Genetically engineered mice express fluorescently tagged proteins at synapses (PSD95, SAP102).
  • Enabled visualization and quantification of synapses across the entire mouse brain.
  • High-resolution confocal and super-resolution microscopy used.

• Findings

  • Identified 37 synapse types using just two proteins—suggests potential for thousands more.
  • Different brain regions have unique synaptic “signatures.”
  • Highest synaptic diversity was found in brain areas associated with cognition (cortex, hippocampus).

"For every single [synapse], we looked at how much of these different proteins... their size and shape... for the first time in any organism... to create a synapse map across the whole nervous system."
—Dr. Seth Grant (11:35)

• Web Tools
  • "Synaptome Explorer" application allows researchers to visualize and analyze synapse data, akin to a "Google Maps" for synapses.

4. Synaptic Diversity: Functional and Evolutionary Perspectives

• Evolution

  • Vertebrates have greater synaptic molecular complexity than invertebrates due to genome duplications.
  • Invertebrate nervous systems, like lobsters, have less diversity.

• Functional Implications

  • Different synapses respond differently to patterns of neural activity, suggesting a more nuanced mechanism for memory storage and recall.
  • Model proposes memory recall relies on patterns of synaptic activity engaging diverse synapses, rather than just long-term stable strength.

"If the molecular composition of synapses controls how it responds to patterns of activity, then if I change the molecular composition of a synapse, then it'll change how it responds to a pattern of activity... Most people study how information is stored, but... it's quite mysterious how information is actually recalled."
—Dr. Seth Grant (24:00)

5. Challenging Established Theories of Memory

• Traditional Model: Focus on long-term potentiation (LTP) and synaptic strength.

• Grant’s Model: Synaptic diversity and response to temporal activity patterns are central; theoretical framework accounts for “recall” dynamics.

• Experimental Support

  • Large-scale genetic studies handled by mutation of synaptic proteins.
  • Observed "genetic dissociation": long-term potentiation can be separated from learning, questioning LTP’s exclusivity in memory.

"We did this big genetic study where we made lots of gene mutations... and we found that we could dissociate [LTP from learning] with 45 different genes... suggesting the long-term change in stable strength isn't really the key thing, and it's this other potential model that we're suggesting."
—Dr. Seth Grant (27:20)

6. Synaptic Mapping and Mental Disorders

• Synaptome Mapping in Disease Models:
  • Applied to mouse models with mutations relevant to schizophrenia and autism.
  • Result: these mutations led to widespread changes in synaptome maps—implying that neuropsychiatric disorders may affect broad brain regions, not just focal spots.
  • Raises possibilities for new therapeutic approaches targeting synaptic diversity.

"We measured this synaptome map... and the answer to both of those questions is yes [the gene mutations do change the brain maps and synapse diversity]."
—Dr. Seth Grant (28:33)

7. Technical Advances in Microscopy and Big Data

• Confocal microscopy: ~200-300nm resolution; enables detection of fluorescent synaptic proteins.
• Super-resolution microscopy: <100nm possible, allows viewing protein distributions within synapses.
• Computational tools and open-source data critical for ongoing research and collaboration.

8. The Relationship to the Connectome

• Connectome: Anatomical wiring diagram (where neurons connect in the brain).
• Synaptome: Molecular map—shows how synapses are constructed, not just where they are.
• Connects to genomics; provides bridge from genetics to brain function, which the “connectome” alone cannot.

"The connectome is really sort of the wiring diagram... but it's actually the synapses, which are at the point of the connections between them... In our case, we're actually telling about the molecules that are within them... the synaptome we can connect to the genome, whereas at present, the connectome isn't really connected to the genome at all."
—Dr. Seth Grant (34:15)

9. Practical Applications and Future Directions

• Mapping additional synaptic proteins to build complete synaptome maps.
• Applying tools to disease models, aging, and behavioral neuroscience.
• Committing to open-access resources and tools like Synaptome Explorer to democratize research.

10. Career Reflections and Advice

• Innovation often faces resistance in funding processes; persistence and vision are key.
• Dr. Grant encourages students to leverage open tools for independent projects, noting strong support for making technology and data accessible.

"Every single one [of my impactful papers] has been met prior... with rejection. When I've written things that have been fairly sort of mediocre, they have been well accepted. So I think that's a real pattern..."
—Dr. Seth Grant (47:43)

Notable Quotes & Moments

• On the Computational Power of Synapses:
  "The synapse we now think of as a molecular computer."
  —Dr. Seth Grant (05:06)

• On Unique Synapse Types:
  "No two synapses are identical... That means they have different functions."
  —Dr. Seth Grant (10:13)

• On Memory and Recall:
  "Most people study how information is stored. But frankly, I think it's quite mysterious how information is actually recalled. I mean, how does it pop out when you recognize something?" —Dr. Seth Grant (25:34)

• On Diversity and Evolution:
  "The duplication event led to the generation of a more complex synaptome map and more diversity of synapses, which is characteristic of the vertebrate."
  —Dr. Seth Grant (20:18)

• On Scientific Collaboration:
  "You can put together a project that no individual could possibly do... it's always very exciting to work with them as a team."
  —Dr. Seth Grant (46:16)

Timestamps for Key Segments

| Time | Segment | |-----------|-------------------------------------------| | 00:04 | Episode intro and guest introduction | | 02:50 | Genes to Cognition program overview | | 04:23 | Postsynaptic proteins and synaptic function| | 06:11 | Gene mutation studies in synapses | | 08:26 | Genetic engineering for visualizing synapses| | 09:50 | Synapse diversity and new models | | 11:35 | Mapping the mouse synaptome | | 13:01 | Number of synapse types and implications | | 14:14 | Brain region-specific synapse signatures | | 17:34 | Integration with Allen Brain Atlas | | 19:35 | Viewing synapses with Synaptome Explorer | | 20:18 | Molecular diversity—vertebrates vs. invertebrates| | 23:30 | Synapse diversity and new memory models | | 27:20 | Genetic dissociation: LTP vs. learning | | 28:33 | Synaptome mapping in schizophrenia & autism| | 31:38 | Advances in microscopy | | 34:15 | Synaptome vs. connectome | | 38:21 | Potential for hallucinations via synaptome differences| | 41:40 | Memories as movies, not snapshots | | 42:36 | Career trajectory and future directions | | 45:03 | Next steps: expanding synaptome mapping | | 47:43 | Advice for young scientists/funding | | 49:12 | Student involvement and tool accessibility| | 50:31 | Where to find Dr. Grant’s work |

Further Resources

• Open-access papers and synaptome data/tools: See brainsciencepodcast.com and referenced links in the episode notes.
• Synaptome Explorer: Tool for exploring the mouse brain synaptome.
• Related scientific resources: Allen Institute for Brain Science (reference atlas integration).

This episode delivers a fascinating deep dive into how the “molecular architecture” of synapses may hold the keys to understanding cognition, learning, neurological disease, and the very uniqueness of individual brains. Dr. Grant’s approachable insights and real-world research examples make this complex topic remarkably accessible for all listeners.