Synapse Diversity and the Dynamic Synaptome Architecture

What is the Synaptome and synapse diversity

• The synaptome refers to the complete set of synapses in the brain, including their molecular makeup and distribution.

What can synapse proteome be used for

Targeting genetic disorders

What are the three foundational ideas for understanding how synapses influence behavior and disease.

• Proteome complexity: The brain’s synapses are composed of highly complex protein compositions.

• Synapse diversity: Different synapses = distinct molecular signatures.

• Synaptome architecture: The structural and functional arrangement of all synapses in the brain.

What is the Hierarchical Molecular Logic (3)

• Core Idea: Synapses are organized in a hierarchical molecular structure = different combinations of proteins (e.g., scaffolding proteins, receptors) = define synapse types and subtypes.

• Significance: This underlies how synapse types relate to specific functions, giving rise to behavior and memory capacity.

What is Behaviour and Synapse Variation (5)

• Innate vs. learned behavior: Synapse architecture supports both.

• Lifespan changes: Synapse composition evolves over time (development to aging).

• Sex differences: Male and female brains show synaptic variation.

• Disorders: Altered synaptome structure is implicated in neurological and psychiatric diseases.

• Implication: Understanding synapse diversity can explain individual differences and susceptibility to disorders.

Synapse Combinations Control Behavior

Combinations of proteins correlate with specific behavioral phenotypes.

Theory of Synapse Diversity (7)

How It Works

• Synapse diversity leads to functional specialization.

Information Capacity

• The brain stores immense amounts of information due to synapse heterogeneity.

Diversity in Cognitive Areas

• Cortex and hippocampus show highest diversity, correlating with cognitive complexity.

Postnatal Synapse Expansion

• Cizeron et al. (2020): Synaptic diversity increases postnatally to match behavioral development.

Molecular Memory and Lifespan Effects (7)

Memory Duration

• Controlled by protein lifetime—some synaptic proteins persist longer than others.

Protein Turnover Rates

• Long protein lifetimes = long-term memory; short = fast adaptation.

Cortex Enrichment

• Cortex is rich in long-lifetime proteins, matching its role in long-term memory.

Lifespan Synaptome

• The synaptome changes from early development through aging.

Synapse Loss with Aging

• Cizeron et al. (2020): aging causes brain-wide synapse subtype loss, with some types being more resilient.

Subtype Vulnerability

• Aging-resilient subtypes retain density; aging-vulnerable ones decline.

Memory & Forgetting

• Linked to the balance of synapse resilience, turnover, and molecular decay.

Disease and the Synaptome (4)

Short vs. Long-Term Synapses

• SPL (short protein lifetime) = short-term memory = Rapid proteostasis

• LPL (long protein lifetime) = long-term memory = Slow proteostasis

Disease Targeting

• Specific synapse types are targeted in neuropsychiatric and developmental disorders.

Mapping Disease to Synaptome

• Different diseases affect distinct synapse types, not just overall synapse count.

Summary on Disease

• Disorders map onto synapse diversity, underscoring the value of synaptome models for diagnosis.

Final Models (4)

Principle 1: Selective Targeting

• Neural activity sculpts specific synapse types/subtypes.

Principle 2: Distributed Effects

• Experience, disease, lifespan, and sex affect the synaptome brain-wide.

Implications for Mutation & Evolution

• Mutations selectively affect synapse types, driving disease but also evolutionary adaptation.

Takeaway

• Synaptome diversity provides the molecular basis for cognition, behavior, memory, plasticity, disease, and even individuality.

Synapse Diversity as Information Storage

• Diverse synapses = high storage potential.

• Different synapses respond to different temporal patterns of activity (e.g., spike trains), effectively encoding “mental movies.”

Protein Lifetime & Memory Duration

• Long-lived proteins in certain synapse types (especially cortical and hippocampal) store long-term memory.

• Short-lived proteins enable short-term adaptability.

Development to Aging

• Postnatal expansion of synapse diversity supports increasing behavioral complexity.

• Aging causes selective synapse loss—certain subtypes are vulnerable, others resilient.

Environmental Enrichment (EE) vs. Standard Condition

• EE does not increase total synapse count, but alters 3.26% of synapses, particularly affecting deep cortical layers.

• Changes are distributed brain-wide, but specific subtypes are selectively increased or decreased.

Sex Differences

• Clear male vs. female differences in synapse density and subtype composition.

• Environment further modifies these sex-based differences, indicating a plasticity-modulated dimorphism.

Disease Implications

• The synapse proteome is heavily burdened by disease: 41% of postsynaptic and 44% of presynaptic proteins are linked to genetic mutations.

• Neurological and psychiatric conditions are strongly associated with specific synapse types, not just general synapse loss.

Synaptome vs. Synaptic Plasticity Models

• Traditional models (e.g., Hebbian plasticity, Kandel’s work) emphasize synaptic strength changes.

• The synaptome model emphasizes diversity and architecture, providing better explanations for:

  • How memories are stored/recalled

  • How aging impacts function

  • Why specific diseases affect specific circuits