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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

Calcium permeability–enhancing mutations in GluRIIC suppress sustained presynaptic homeostatic plasticity triggered by loss of GluRIIA

  • Olfat A. Malak1,2
  • Lindsay Gray1,3
  • Ammar Aly1,4
  • Robin W. Ball5,6
  • Jessica Gustin-Murray6,7
  • Myriam Moujahidine1,5
  • Guadalupe Carrasco1
  • Andrew Rosko1
  • Ehud Y. Isacoff6,7,8
  • A. Pejmun Haghighi1,4,5
8 affiliations
  1. 1Buck Institute for Research on Aging, Novato, CA 94945
  2. 2Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
  3. 3Inscopix Inc., Mountain View, CA 94043
  4. 4Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089
  5. 5Department of Physiology, McGill University, Montreal, QC H3G1Y6, Canada
  6. 6Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720
  7. 7Department of Neuroscience, University of California, Berkeley, CA 94720
  8. 8Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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Abstract

Presynaptic homeostatic plasticity (PHP) stabilizes neural circuits by adjusting synaptic strength when faced with disturbances in postsynaptic activity. Despite identification of many genes and mechanisms required for PHP, the underlying trigger mechanisms remain elusive. Loss of GluRIIA, one of five glutamate receptor subunits at the Drosophila neuromuscular junction (NMJ), reduces quantal size and synaptic calcium influx and triggers a sustained PHP. Two common features of genetic manipulations that lead to the activation of this form of PHP are a drop in synaptic calcium influx and a reduction in quantal size; however, it is not clear that either of these features is absolutely necessary for PHP. We have generated a glutamate receptor transgene with mutations in the pore, which can largely restore calcium influx in GluRIIA−/− mutant larvae without affecting quantal size. We find that restoration of calcium influx in GluRIIA−/− mutant larvae blocks PHP without any detectable changes in synaptic structure. Our findings, therefore, indicate that a reduction in synaptic calcium influx is necessary for triggering and/or maintenance of the sustained PHP at the NMJ, a model that may be extendable to the vertebrate NMJ and neuron–neuron synapses.

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Cite

BibTeXRIS
BibTeX
@article{malak2026calcium,
  title = {{Calcium permeability–enhancing mutations in GluRIIC suppress sustained presynaptic homeostatic plasticity triggered by loss of GluRIIA}},
  author = {Olfat A. Malak and Lindsay Gray and Ammar Aly and Robin W. Ball and Jessica Gustin-Murray and Myriam Moujahidine and Guadalupe Carrasco and Andrew Rosko and Ehud Y. Isacoff and A. Pejmun Haghighi},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2625954123},
  url = {https://doi.org/10.1073/pnas.2625954123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Calcium permeability–enhancing mutations in GluRIIC suppress sustained presynaptic homeostatic plasticity triggered by loss of GluRIIA
AU  - Olfat A. Malak
AU  - Lindsay Gray
AU  - Ammar Aly
AU  - Robin W. Ball
AU  - Jessica Gustin-Murray
AU  - Myriam Moujahidine
AU  - Guadalupe Carrasco
AU  - Andrew Rosko
AU  - Ehud Y. Isacoff
AU  - A. Pejmun Haghighi
PY  - 2026
DA  - 2026/10/27
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2625954123
UR  - https://doi.org/10.1073/pnas.2625954123
AB  - Presynaptic homeostatic plasticity (PHP) stabilizes neural circuits by adjusting synaptic strength when faced with disturbances in postsynaptic activity. Despite identification of many genes and mechanisms required for PHP, the underlying trigger mechanisms remain elusive. Loss of GluRIIA, one of five glutamate receptor subunits at the Drosophila neuromuscular junction (NMJ), reduces quantal size and synaptic calcium influx and triggers a sustained PHP. Two common features of genetic manipulations that lead to the activation of this form of PHP are a drop in synaptic calcium influx and a reduction in quantal size; however, it is not clear that either of these features is absolutely necessary for PHP. We have generated a glutamate receptor transgene with mutations in the pore, which can largely restore calcium influx in GluRIIA−/− mutant larvae without affecting quantal size. We find that restoration of calcium influx in GluRIIA−/− mutant larvae blocks PHP without any detectable changes in synaptic structure. Our findings, therefore, indicate that a reduction in synaptic calcium influx is necessary for triggering and/or maintenance of the sustained PHP at the NMJ, a model that may be extendable to the vertebrate NMJ and neuron–neuron synapses.
SN  - 0027-8424
SN  - 1091-6490
ER  -