The classical complement cascade mediates CNS synapse elimination.
During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.
Stevens
Beth
B
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA. beths@standfordmedalumni.org
Allen
Nicola J
NJ
Vazquez
Luis E
LE
Howell
Gareth R
GR
Christopherson
Karen S
KS
Nouri
Navid
N
Micheva
Kristina D
KD
Mehalow
Adrienne K
AK
Huberman
Andrew D
AD
Stafford
Benjamin
B
Sher
Alexander
A
Litke
Alan M
AM
Lambris
John D
JD
Smith
Stephen J
SJ
John
Simon W M
SW
Barres
Ben A
BA
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D002490:Central Nervous System / Q000502:physiology*; D003167:Complement Activation; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism*; D005829:Geniculate Bodies / Q000502:physiology; D005901:Glaucoma / Q000378:metabolism*; D036881:Long-Term Synaptic Depression; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013569:Synapses; D015854:Up-Regulation
D003176:Complement C3; D012333:RNA, Messenger; D015922:Complement C1q