Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression

Joshua C. Brown, Amber Petersen, Ling Zhong, Miranda L. Himelright, Jessica A. Murphy, Randall S. Walikonis and Nashaat Z. Gerges ()
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Joshua C. Brown: Neurobiology and Anatomy, The Medical College of Wisconsin
Amber Petersen: Neurobiology and Anatomy, The Medical College of Wisconsin
Ling Zhong: Neurobiology and Anatomy, The Medical College of Wisconsin
Miranda L. Himelright: University of Connecticut
Jessica A. Murphy: University of Connecticut
Randall S. Walikonis: University of Connecticut
Nashaat Z. Gerges: Neurobiology and Anatomy, The Medical College of Wisconsin

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11080

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