Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Activating transcription factor 4 (ATF4) has conflicting roles in neuronal plasticity and memory.
• The cellular mechanisms underlying ATF4's functions in the brain remain unclear.

Purpose of the Study:

• To investigate ATF4's role in postsynaptic synapse development and dendritic spine morphology.
• To elucidate the cellular and molecular mechanisms of ATF4 action in neurons.

Main Methods:

• shRNA-mediated knockdown of ATF4 in cultured cortical and hippocampal neurons.
• In vivo knockdown of ATF4 in adult mouse hippocampal neurons.
• Analysis of synaptic markers (PSD-95, GluR1) and dendritic spine morphology.
• Assessment of Cdc42 protein stability and expression.

Main Results:

• ATF4 silencing reduced excitatory synapse markers (PSD-95, GluR1) and mushroom spine density, while increasing filopodia.
• ATF4 knockdown decreased Cdc42 protein half-life and expression.
• Knockdown of Cdc42 mimicked ATF4 knockdown effects on spines and synapses.
• ATF4 overexpression did not alter synapse or spine densities.

Conclusions:

• ATF4 is essential for proper postsynaptic development and dendritic spine morphology.
• ATF4 regulates synapse and spine density, at least partly, by controlling Cdc42 stability and expression.
• ATF4's transcriptional activity is required for its effects on synaptic structures.