title: Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression.
abstract: Dysfunction of the proteins regulating synaptic function can cause synaptic plasticity imbalance that underlies neurological disorders such as intellectual disability. A study found that four distinct mutations within BRAG1, an Arf-GEF synaptic protein, each led to X-chromosome-linked intellectual disability (XLID). Although the physiological functions of BRAG1 are poorly understood, each of these mutations reduces BRAG1's Arf-GEF activity. Here we show that BRAG1 is required for the activity-dependent removal of AMPA receptors in rat hippocampal pyramidal neurons. Moreover, we show that BRAG1 bidirectionally regulates synaptic transmission. On one hand, BRAG1 is required for the maintenance of synaptic transmission. On the other hand, BRAG1 expression enhances synaptic transmission, independently of BRAG1 Arf-GEF activity or neuronal activity, but dependently on its C-terminus interactions. This study demonstrates a dual role of BRAG1 in synaptic function and highlights the functional relevance of reduced BRAG1 Arf-GEF activity as seen in the XLID-associated human mutations.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin 53132 USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Brown
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin 53132 USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Petersen
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin 53132 USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269 USA.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Himelright
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269 USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Murphy
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269 USA.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Walikonis
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin 53132 USA.
authors.forename: Nashaat Z
authors.initials: NZ
authors.lastname: Gerges
mesh_terms: D000595:Amino Acid Sequence; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036881:Long-Term Synaptic Depression; D018091:Receptors, AMPA / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D018091:Receptors, AMPA; C000588810:IQSEC1 protein, rat; C516347:Iqsec2 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2