ADAR2-mediated Q/R editing of GluA2 in homeostatic synaptic plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Homeostatic synaptic plasticity adjusts neuronal activity via synaptic strength modulation.
• Activity deprivation increases synaptic strength by incorporating more AMPA receptors (AMPARs), especially Ca2+-permeable ones.

Purpose of the Study:

• To investigate the role of posttranscriptional editing of GRIA2 mRNA in homeostatic synaptic plasticity.
• To elucidate the mechanism by which Ca2+-permeable AMPARs are increased during activity deprivation.

Main Methods:

• Cultured neurons and mice were used to study synaptic plasticity.
• Techniques included monitoring GRIA2 mRNA editing, ADAR2 activity, AMPAR expression, and neuronal activity.
• CRISPR-Cas13 and viral overexpression were employed to manipulate gene editing and ADAR2 levels.

Main Results:

• Activity deprivation decreased posttranscriptional editing of GRIA2 mRNA, leading to more unedited GluA2 subunits (Q-codon) and increased Ca2+-permeable AMPARs at synapses.
• This was mediated by reduced nuclear ADAR2 abundance and activity.
• Overexpression of ADAR2 or direct editing of GluA2 transcripts inhibited homeostatic upscaling.
• In mice, dark rearing decreased GluA2 editing in V1, and ADAR2 overexpression blocked plasticity induction.

Conclusions:

• Activity-dependent regulation of GluA2 RNA editing is a key mechanism controlling homeostatic synaptic plasticity.
• Decreased ADAR2 activity leads to increased Ca2+-permeable AMPARs, enhancing synaptic strength during reduced neuronal activity.