TY - JOUR
T1 - Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
AU - Genç, Özgür
AU - An, Joon Yong
AU - Fetter, Richard D.
AU - Kulik, Yelena
AU - Zunino, Giulia
AU - Sanders, Stephan J.
AU - Davis, Graeme W.
N1 - Funding Information:
Supported by NINDS Grant (R35-NS097212) and Simons Foundation (SFARI #401636) to GWD, Simons Foundation (SFARI #402281) and NIMH (R01 MH110928) to SJS, and NRF-2017M3C7A1026959 to J-YA. We thank Matt State for comments and support and members of the Davis, State and Sanders labs for critical evaluation of the manuscript.
Funding Information:
Supported by NINDS Grant (R35-NS097212) and Simons Foundation (SFARI #401636) to GWD, Simons Foundation (SFARI #402281) and NIMH (R01 MH110928) to SJS, and NRF 2017M3C7A1026959 to J-YA. We thank Matt State for comments and support and members of the Davis, State and Sanders labs for critical evaluation of the manuscript. National Institute of Neurological Disorders and- Stroke R35-NS097212-Graeme W Davis, Simons Foundation -SFARI #401636- Graeme W Davis, Simons Foundation- SFARI #402281- Stephan J Sanders, National Institute of Mental Health -R01 MH110928 -Stephan J Sanders, Neurosciences Research Foundation -2017M3C7A1026959- Joon-Yong An.
Publisher Copyright:
© Genç et al.
PY - 2020/7
Y1 - 2020/7
N2 - We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.
AB - We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.
UR - http://www.scopus.com/inward/record.url?scp=85089126391&partnerID=8YFLogxK
U2 - 10.7554/eLife.55775
DO - 10.7554/eLife.55775
M3 - Article
C2 - 32609087
AN - SCOPUS:85089126391
SN - 2050-084X
VL - 9
SP - 1
EP - 32
JO - eLife
JF - eLife
M1 - e55775
ER -