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When an action potential reaches the presynaptic axon terminal, it releases neurotransmitters from the neuron into the synaptic cleft at a chemical synapse. The released neurotransmitter can be excitatory or inhibitory. The critical criteria commonly used to determine whether a molecule is a neurotransmitter at a chemical synapse are the molecule's presence in the presynaptic neuron. Second, its release is in response to strong presynaptic depolarization. And lastly, the presence of...
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Synaptic integration mainly includes the summation of graded potentials. Graded potentials, regardless of their type, cause subtle alterations in membrane voltage, resulting in either depolarization or hyperpolarization. These incremental changes, when combined or summed, can propel the neuron toward its threshold. Consider, for example, a membrane experiencing a +15 mV shift, causing it to depolarize from -70 mV to -55 mV. In this scenario, graded potentials govern the membrane's ability...
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Related Experiment Video

Updated: May 27, 2025

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A toolbox for ablating excitatory and inhibitory synapses.

Aida Bareghamyan1,2, Changfeng Deng3, Sarah Daoudi1

  • 1Department of Biology, Division of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.

Biorxiv : the Preprint Server for Biology
|February 20, 2025
PubMed
Summary

Researchers developed novel genetic tools to precisely control neural circuit structure by degrading synaptic proteins. These tools enable targeted ablation of excitatory and inhibitory synapses, offering new ways to study brain function.

Keywords:
E3 ligaseGephyrinPSD-95ablationphotoactivatablesynapse

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Optogenetics and chemogenetics allow manipulation of neuronal activity but not neural circuit structure.
  • Existing tools lack methods for targeted structural modification of neural circuits.

Purpose of the Study:

  • To develop genetically encoded tools for targeted ablation of synaptic structures.
  • To create specific, reversible tools for manipulating neural circuit architecture.

Main Methods:

  • Designed E3 ligase-dependent protein degradation systems.
  • Developed constitutive (PFE3), light-inducible (paGFE3), and chemically-inducible (chGFE3) tools.
  • Utilized protein targeting to synaptic scaffolding proteins (PSD-95, Gephyrin) for degradation.

Main Results:

  • PFE3 enabled constitutive ablation of excitatory synapses by degrading PSD-95.
  • paGFE3 used a photoactivatable complex to ablate inhibitory synapses via Gephyrin degradation upon light exposure.
  • chGFE3 achieved chemically induced ablation of inhibitory synapses using a dimerizer system.

Conclusions:

  • Introduced three novel genetic tools for precise, reversible manipulation of neural circuit structure.
  • These tools facilitate targeted synaptic ablation, enabling detailed study of neural circuit function.
  • The developed methods offer new possibilities for dissecting complex neural networks.