Durable fear memories require PSD-95

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• Traumatic fear memories are persistent and dynamic, contributing to anxiety disorders.
• The neural and molecular mechanisms of fear memory durability are not fully understood.
• Postsynaptic density 95 (PSD-95) is a key synaptic protein involved in memory.

Purpose of the Study:

• To investigate the role of PSD-95 in fear memory formation, retrieval, and maintenance.
• To identify the neural basis of PSD-95's contribution to memory durability.

Main Methods:

• Utilized a loss-of-function mutant mouse (PSD-95(GK)) lacking the guanylate kinase domain of PSD-95.
• Employed ex vivo immediate-early gene mapping, in vivo neuronal recordings, and viral-mediated knockdown (KD).
• Focused on the infralimbic (IL) cortex, anterior cingulate cortex (ACC), and prelimbic cortex.

Main Results:

• PSD-95 is dispensable for recent fear memory but essential for precise, flexible, and remote fear memories.
• PSD-95(GK) mice showed impaired remote memory retrieval linked to hypoactivation and altered neuronal activity in the IL cortex.
• PSD-95 KD in the IL cortex impaired fear extinction and remote memory, affecting IL dendritic spines.

Conclusions:

• PSD-95 in the IL cortex is critical for the durability of fear memories.
• These findings suggest PSD-95 as a potential therapeutic target for anxiety disorders characterized by persistent fear memories.