Rapid ATF4 Depletion Resets Synaptic Responsiveness after cLTP

Area of Science:

• Neuroscience
• Molecular Biology

Background:

• Activating transcription factor 4 (ATF4) is known for its role in stress responses.
• Its physiological functions in learning and memory are not well-defined, with differing views.
• ATF4 is proposed to regulate excitability during synaptic plasticity.

Purpose of the Study:

• To investigate the role of ATF4 in synaptic plasticity.
• To determine how ATF4 protein levels change during chemically induced long-term potentiation (cLTP).
• To elucidate the physiological significance of ATF4 depletion during synaptic plasticity.

Main Methods:

• Used mature hippocampal cultures subjected to a cLTP protocol.
• Measured ATF4 protein and mRNA levels following cLTP induction.
• Utilized ATF4 overexpression to assess its role in synaptic recovery.
• Employed a transcriptionally inactive ATF4 mutant to confirm findings.

Main Results:

• ATF4 protein, not mRNA, was rapidly depleted by ~50% after cLTP induction via NMDA receptor activation.
• ATF4 depletion occurred in dendrites and cell bodies, correlating with phospho-eIF2a depletion, suggesting reduced translation.
• Constitutive overexpression of ATF4 blocked the recovery of synaptic activity and AMPA receptor density post-cLTP.
• This blockade was not observed with a transcriptionally inactive ATF4 mutant.

Conclusions:

• ATF4 protein depletion is a key event during synaptic plasticity.
• ATF4 plays a necessary role in resetting baseline synaptic responsiveness after cLTP.
• Regulation of ATF4 levels is crucial for synaptic plasticity and potentially learning and memory.