Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling. Issue 12 (10th July 2014)

• Record Type: Journal Article
• Authors: Diniz, Luan Pereira; Tortelli, Vanessa; Garcia, Matheus Nunes; Araújo, Ana Paula Bérgamo; Melo, Helen M.; Seixas da Silva, Gisele S.; De Felice, Fernanda G.; Alves‐Leon, Soniza Vieira; de Souza, Jorge Marcondes; Romão, Luciana Ferreira; Castro, Newton Gonçalves; Gomes, Flávia Carvalho Alcantara
• Is Part Of: Glia. Volume 62:Issue 12(2014:Dec.)
• Page Start: 1917
• Page End: 1931
• Publication Date: 2014-07-10
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22713
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic> and <italic>in vivo</italic>. 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. GLIA 2014;62:1917–1931</p> </abstract>