title: Subunit-selective N-Methyl-d-aspartate (NMDA) Receptor Signaling through Brefeldin A-resistant Arf Guanine Nucleotide Exchange Factors BRAG1 and BRAG2 during Synapse Maturation.
abstract: The maturation of glutamatergic synapses in the CNS is regulated by NMDA receptors (NMDARs) that gradually change from a GluN2B- to a GluN2A-dominated subunit composition during postnatal development. Here we show that NMDARs control the activity of the small GTPase ADP-ribosylation factor 6 (Arf6) by consecutively recruiting two related brefeldin A-resistant Arf guanine nucleotide exchange factors, BRAG1 and BRAG2, in a GluN2 subunit-dependent manner. In young cortical cultures, GluN2B and BRAG1 tonically activated Arf6. In mature cultures, Arf6 was activated through GluN2A and BRAG2 upon NMDA treatment, whereas the tonic Arf6 activation was not detectable any longer. This shift in Arf6 regulation and the associated drop in Arf6 activity were reversed by a knockdown of BRAG2. Given their sequential recruitment during development, we examined whether BRAG1 and BRAG2 influence synaptic currents in hippocampal CA1 pyramidal neurons using patch clamp recordings in acute slices from mice at different ages. The number of AMPA receptor (AMPAR) miniature events was reduced by depletion of BRAG1 but not by depletion of BRAG2 during the first 2 weeks after birth. In contrast, depletion of BRAG2 during postnatal weeks 4 and 5 reduced the number of AMPAR miniature events and compromised the quantal sizes of both AMPAR and NMDAR currents evoked at Schaffer collateral synapses. We conclude that both Arf6 activation through GluN2B-BRAG1 during early development and the transition from BRAG1- to BRAG2-dependent Arf6 signaling induced by the GluN2 subunit switch are critical for the development of mature glutamatergic synapses.
authors.affiliation: From the Neuroscience Research Center (NWFZ) and Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany and.
authors.forename: Mohammad Nael
authors.initials: MN
authors.lastname: Elagabani
authors.affiliation: From the Neuroscience Research Center (NWFZ) and Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany and.
authors.forename: Dušica
authors.initials: D
authors.lastname: Briševac
authors.affiliation: From the Neuroscience Research Center (NWFZ) and.
authors.forename: Michael
authors.initials: M
authors.lastname: Kintscher
authors.affiliation: the Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Pohle
authors.affiliation: the Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Köhr
authors.affiliation: From the Neuroscience Research Center (NWFZ) and.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmitz
authors.affiliation: From the Neuroscience Research Center (NWFZ) and Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany and hckornau@charite.de.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Kornau
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D020126:Brefeldin A; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C000588810:IQSEC1 protein, rat; C539984:IQSEC2 protein, mouse; C516347:Iqsec2 protein, rat; C121001:NR2B NMDA receptor; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat
keywords: ADP ribosylation factor (ARF); BRAG; GTPase; N-methyl-D-aspartate receptor (NMDA receptor, NMDAR); X chromosome-linked intellectual disability (XLID); guanine nucleotide exchange factor (GEF); neurodevelopment; postsynaptic density (PSD); subunit switch; synapse