Astrocyte-induced synaptogenesis is mediated by transforming growth factor β signaling through modulation of D-serine levels in cerebral cortex neurons.
Assembly of synapses requires proper coordination between pre- and postsynaptic elements. Identification of cellular and molecular events in synapse formation and maintenance is a key step to understand human perception, learning, memory, and cognition. A key role for astrocytes in synapse formation and function has been proposed. Here, we show that transforming growth factor β (TGF-β) signaling is a novel synaptogenic pathway for cortical neurons induced by murine and human astrocytes. By combining gain and loss of function approaches, we show that TGF-β1 induces the formation of functional synapses in mice. Further, TGF-β1-induced synaptogenesis involves neuronal activity and secretion of the co-agonist of the NMDA receptor, D-serine. Manipulation of D-serine signaling, by either genetic or pharmacological inhibition, prevented the TGF-β1 synaptogenic effect. Our data show a novel molecular mechanism that might impact synaptic function and emphasize the evolutionary aspect of the synaptogenic property of astrocytes, thus shedding light on new potential therapeutic targets for synaptic deficit diseases.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, RJ, Brazil.
Luan Pereira
LP
Diniz
Juliana Carvalho
JC
Almeida
Vanessa
V
Tortelli
Charles
C
Vargas Lopes
Pedro
P
Setti-Perdigão
Joice
J
Stipursky
Suzana Assad
SA
Kahn
Luciana Ferreira
LF
Romão
Joari
J
de Miranda
Soniza Vieira
SV
Alves-Leon
Jorge Marcondes
JM
de Souza
Newton G
NG
Castro
Rogério
R
Panizzutti
Flávia Carvalho Alcantara
FC
Gomes
D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003071:Cognition; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004594:Electrophysiology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012694:Serine / Q000737:chemistry*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D017077:Culture Media, Conditioned; D016212:Transforming Growth Factor beta; D012694:Serine