Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
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 no...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/55775 |
| _version_ | 1811236818056642560 |
|---|---|
| author | Özgür Genç Joon-Yong An Richard D Fetter Yelena Kulik Giulia Zunino Stephan J Sanders Graeme W Davis |
| author_facet | Özgür Genç Joon-Yong An Richard D Fetter Yelena Kulik Giulia Zunino Stephan J Sanders Graeme W Davis |
| author_sort | Özgür Genç |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:14:39Z |
| format | Article |
| id | doaj.art-814331ba5bae4ff7bb04373020dc0b49 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:14:39Z |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-814331ba5bae4ff7bb04373020dc0b492022-12-22T03:33:27ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.55775Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiersÖzgür Genç0https://orcid.org/0000-0003-0635-3192Joon-Yong An1Richard D Fetter2Yelena Kulik3Giulia Zunino4Stephan J Sanders5Graeme W Davis6https://orcid.org/0000-0003-1355-8401Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United StatesDepartment of Psychiatry UCSF Weill Institute for Neurosciences University of California, San Francisco, San Francisco, United States; School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of KoreaDepartment of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United StatesDepartment of Psychiatry UCSF Weill Institute for Neurosciences University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United StatesWe 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.https://elifesciences.org/articles/55775autismCHD8homeostatic plasticityneurotransmissionpresynapticCREG |
| spellingShingle | Özgür Genç Joon-Yong An Richard D Fetter Yelena Kulik Giulia Zunino Stephan J Sanders Graeme W Davis Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers eLife autism CHD8 homeostatic plasticity neurotransmission presynaptic CREG |
| title | Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers |
| title_full | Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers |
| title_fullStr | Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers |
| title_full_unstemmed | Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers |
| title_short | Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers |
| title_sort | homeostatic plasticity fails at the intersection of autism gene mutations and a novel class of common genetic modifiers |
| topic | autism CHD8 homeostatic plasticity neurotransmission presynaptic CREG |
| url | https://elifesciences.org/articles/55775 |
| work_keys_str_mv | AT ozgurgenc homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT joonyongan homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT richarddfetter homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT yelenakulik homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT giuliazunino homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT stephanjsanders homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers AT graemewdavis homeostaticplasticityfailsattheintersectionofautismgenemutationsandanovelclassofcommongeneticmodifiers |