Abstract
Background
Impairment of synaptic plasticity is closely correlated with a range of pathological
conditions, such as cognitive deficits. However, how synaptic efficacy is regulated
remains incompletely understood. Here, we report that the epigenetic factor JADE2
was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive
functions in mice.
Methods
We used the Morris water maze and the fear conditioning test to examine learning-related
behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA
sequencing, and electrophysiological recordings were used to address our questions.
Results
JADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo.
Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity,
leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates
hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2
modulates synaptic functions mainly by transcriptional activation of cytoskeletal
regulator Rac1, and this activity is dependent on its interaction with histone acetyltransferase
HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related
behaviors.
Conclusions
Our findings reveal that JADE2 plays a critical role in regulating synaptic plasticity
and memory formation, suggesting that activity-dependent epigenetic regulation is
an important molecular mechanism in controlling synaptic plasticity.
Keywords
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Article Info
Publication History
Published online: May 22, 2022
Accepted:
May 11,
2022
Received in revised form:
April 20,
2022
Received:
January 10,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Society of Biological Psychiatry.
