Kdm4a is an activity downregulated barrier to generate engrams for memory separation

Area of Science:

• Neuroscience
• Epigenetics
• Molecular Biology

Background:

• Memory engrams, subsets of activated neurons, are crucial for memory processes.
• Epigenetic factors can influence memory formation, but the mechanisms of engram selection are unclear.

Purpose of the Study:

• To identify factors controlling memory engram formation using CRISPR screening in the hippocampus.
• To elucidate the role of histone lysine-specific demethylase 4a (Kdm4a) in regulating engram allocation and plasticity.

Main Methods:

• CRISPR screening in the hippocampus to identify epigenetic regulators of engram formation.
• Investigated the interaction of Kdm4a with Trpm7 gene loci and its effect on transcription.
• Utilized genetic manipulation and artificial neural activation to assess Kdm4a's impact on rodent behavior.

Main Results:

• Identified Kdm4a as a negative regulator of memory engram formation.
• Kdm4a is downregulated upon neural activation and influences mossy fiber bouton volume.
• Kdm4a anchors to Trpm7 gene loci, regulating Trpm7 burst transcription via nascent RNA stalling.
• YTH domain containing protein 2 (Ythdc2) facilitates Kdm4a recruitment and RNA stabilization at the Trpm7 locus.
• Reduced Kdm4a expression in the hippocampus improved pattern separation in rodents.

Conclusions:

• Kdm4a acts as a critical negative regulator of memory engram formation.
• The Kdm4a-Trpm7 pathway provides a mechanism for priming neural circuits for distinct memory formation.
• Targeting Kdm4a may offer therapeutic potential for enhancing memory and cognitive functions.