Overview
This lecture explains how synaptic pruning refines neural circuits during brain development, its cellular mechanisms, and implications in neurodevelopmental and neurodegenerative diseases.
Synaptic Pruning in Brain Development
- Newborn brains have ~100 billion neurons, about 15% more than in adulthood.
- Synaptic pruning weakens and removes less-used neural connections, strengthening relevant circuits as we age.
- Pruning transforms a broadly-wired infant brain into specialized mature networks.
- Synapse density increases after birth, peaks at 1-2 years, declines during adolescence, and then stabilizes.
- Selective pruning optimizes brain efficiency and robustness compared to networks without overabundant initial connections.
Mechanisms and Regulation of Pruning
- Pruning is guided by neural activity—active synapses are retained, less-active ones are targeted for removal.
- Microglia, brain immune cells, and immune system proteins (complement proteins, fractalkine) are involved in synapse elimination.
- Complement proteins tag low-activity synapses for microglial destruction.
- Blocking neural activity or complement signals disrupts proper pruning and circuit refinement.
Synaptic Pruning and Disease
- Too much pruning may contribute to schizophrenia (fewer synapses), often during adolescence.
- Too little pruning may be a factor in autism (excess synapses).
- Genetic variants affecting complement component 4 (C4) increase schizophrenia risk by possibly promoting excessive pruning.
- Microglial dysfunction in pruning is implicated in neurodevelopmental disorders.
- Similar immune mechanisms may reactivate in neurodegenerative diseases like Alzheimer’s, leading to synapse loss.
Molecular Insights & Therapeutic Implications
- Major histocompatibility complex class I (MHC-I) and PirB receptor regulate pruning and plasticity.
- In Alzheimer’s models, loss of PirB protects memory even with amyloid plaque buildup.
- Blocking complement signaling in mice mitigates synapse loss and behavioral symptoms.
- Understanding pruning mechanisms may help develop new treatments for neurological disorders.
Key Terms & Definitions
- Synaptic Pruning — selective elimination of unnecessary neural connections during development.
- Microglia — brain-resident immune cells that participate in synapse elimination.
- Complement Proteins — immune proteins that tag synapses for removal.
- Fractalkine — signaling molecule between neurons and microglia.
- Connectopathies — disorders arising from abnormal neural wiring.
- MHC-I — immune molecules involved in neural plasticity and pruning.
- PirB — receptor important for synaptic pruning and implicated in Alzheimer’s.
Action Items / Next Steps
- Review diagrams of neural circuit changes during development.
- Read about complement system roles in the brain for further context.
- Prepare discussion points on how understanding pruning could inform treatments for neurodevelopmental and neurodegenerative diseases.