The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• The integrated stress response (ISR) influences cognition by modulating synaptic plasticity.
• Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is inhibited by ISR blockade and facilitated by ISR activation.
• The role of activating transcription factor 4 (ATF4), a key ISR effector, in mGluR-LTD is unknown.

Purpose of the Study:

• To investigate the role of ATF4 in mGluR-LTD and its underlying molecular mechanisms.
• To determine if ATF4 modulates mitochondrial function in the context of synaptic plasticity.
• To assess the behavioral relevance of ATF4-mediated mGluR-LTD.

Main Methods:

• Pharmacological activation of group I mGluRs in mouse hippocampal slices.
• Analysis of ATF4 protein and mRNA levels.
• Assessment of oxidative phosphorylation (OXPHOS) protein expression.
• Selective deletion of ATF4 in excitatory neurons.
• Inhibition of OXPHOS using a small molecule inhibitor.
• Object-place learning behavioral paradigm in mice.

Main Results:

• Group I mGluR activation increased ATF4 protein levels and downregulated OXPHOS proteins.
• Selective deletion of ATF4 impaired mGluR-LTD and prevented OXPHOS protein downregulation.
• OXPHOS inhibition rescued mGluR-LTD in ATF4-depleted slices.
• ATF4 deletion disrupted object-place learning.

Conclusions:

• ATF4 is a critical mediator of mGluR-LTD, regulating synaptic plasticity through modulation of mitochondrial function.
• ATF4 plays a significant role in learning and memory processes dependent on mGluR-LTD.
• These findings highlight ATF4's involvement in protein synthesis-regulated synaptic depression and associated behaviors.