title: Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling.
abstract: The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission.
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: Luan Pereira
authors.initials: LP
authors.lastname: Diniz
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tortelli
authors.forename: Matheus Nunes
authors.initials: MN
authors.lastname: Garcia
authors.forename: Ana Paula Bérgamo
authors.initials: AP
authors.lastname: Araújo
authors.forename: Helen M
authors.initials: HM
authors.lastname: Melo
authors.forename: Gisele S Seixas da
authors.initials: GS
authors.lastname: Silva
authors.forename: Fernanda G De
authors.initials: FG
authors.lastname: Felice
authors.forename: Soniza Vieira
authors.initials: SV
authors.lastname: Alves-Leon
authors.forename: Jorge Marcondes de
authors.initials: JM
authors.lastname: Souza
authors.forename: Luciana Ferreira
authors.initials: LF
authors.lastname: Romão
authors.forename: Newton Gonçalves
authors.initials: NG
authors.lastname: Castro
authors.forename: Flávia Carvalho Alcantara
authors.initials: FC
authors.lastname: Gomes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D011963:Receptors, GABA-A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D011963:Receptors, GABA-A; D016212:Transforming Growth Factor beta; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D018698:Glutamic Acid; D016202:N-Methylaspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; Neuroligin 2; TGF-β1; astrocyte; inhibitory synapse