Download The Complement System

2/1/2015
The Complement System:
An Unexpected Role in
Synaptic Pruning During
Development and Disease
STEPHAN, BARRES & STEVENS (2012)
Introduction

What is the Classical Complement Cascade?


Complement proteins are “innate immune proteins … associated with the rapid
recognition and elimination of pathogens and harmful cellular debris” (p. 370)
New research is revealing an unexpected role for complement in CNS
development

Esp. in synaptic pruning (i.e. the developmental elimination of extra synapses)
1
2/1/2015
Complement Proteins


What is their function in the immune system?

To clear cellular material that has been marked for elimination

They tag pathogenic microbes for fast elimination by phagocytic
macrophages
Surprisingly, complement proteins have been found in developing
synapses

Microglia and astrocytes are the biggest producers of complement in the CNS
Complement in the developing CNS

Complement components and proteins can be locally produced in the brain

Microglia in the CNS express high levels of C1q, CR3 and CR5


these are complement receptors which are crucial for inducing phagocytosis
Neuronal stem cells express multiple complement receptors

their differentiation and migration is driven by response to complement proteins
2
2/1/2015
Classical Complement Cascade Regulates
Brain Wiring During Development


One example of complement expression in CNS development comes
from retinal ganglion cells (RGC)

Retinal neurons express the C1q gene only in the early postnatal period

This evidence suggests that complement is tagging weak synapses for
elimination in the developing brain
Research on C1q and C3 knockout mice showed defective synaptic
refinement and elimination

Synapses failed to segregate into eye-specific territories

Also showed increase in presynaptic boutons and excitatory connectivity in the
cortex
How are complement-tagged
synapses eliminated?


Evidence points to microglia as key synaptic pruners in developing CNS

Microglia are the only resident brain cells to express CR3 (which tags cells for
elimination in the immune system)

“Activated” microglia have been found in many postnatal brain regions (e.g.
lateral geniculate nucleus, hippocampus, cerebellum and olfactory bulb)
Recent studies have found microglia engulf postsynaptic elements during
synaptic remodeling in hippocampus and visual cortex

Together, these findings suggest that C3 and CR3 interact to mediate active
synaptic pruning
3
2/1/2015
Which synapses are tagged for
elimination?


What determines which synapses will be eliminated during development?

Synapse elimination thought to result from competition between neighboring
axons over postsynaptic territory

“Punishment Model” – strong synapses effectively drive postsynaptic responses
and punish weaker synapses by eliminating them
Does complement tag and punish synapses destined for elimination?

Could be that C1q and C3 preferentially tag weaker synapses

Possibly complement binds to all synapses but only stronger ones can protect
themselves from elimination

Answer is not yet known
Complement Interactions with other
Immune Pathways

In addition to complement, other immune-related molecules contribute
to synaptic refinement

Neuronal Pentraxins (e.g. NP1/2 and NARP) – synaptic proteins; analogous
to immune system proteins which are involved in opsonization and
phagocytosis of dead cells


Neuronal pentraxins may also serve as binding partners for C1q during synapse
development and complement-mediated synaptic pruning
Adaptive Immune System (MHC-I family of proteins and receptors) –
specializes in recognition and removal of foreign antigens

MHC-I genes are highly expressed in brain regions undergoing activitydependent synaptic remodeling
4
2/1/2015
What if there is too much
complement?

Too much complement activation could destabilize neural networks

Upregulated C1q and C3 is often seen in temporal lobe epilepsy in the adult
brain

Maternal infection during pregnancy may activate immune responses in the
fetal brain, altering synaptic development

Postmortem studies have linked abnormal microglial function and/or
complement cascade activation to autism, schizophrenia and other
neuropsychiatric conditions
5