APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Palmitoylation, a lipid modification, is implicated in learning and memory processes.
• The precise mechanisms linking palmitoylation to synaptic function and memory, particularly fear memory, are not fully understood.
• Disorders like PTSD and age-related cognitive decline may involve dysregulated palmitoylation.

Purpose of the Study:

• To investigate the role of palmitoylation in hippocampal synaptic transmission and fear memory formation.
• To explore palmitoylation's involvement in the functional modification of synaptic proteins, including PSD-95 and glutamate receptors.
• To determine the influence of depalmitoylation enzymes on glutamatergic synaptic plasticity.

Main Methods:

• Acyl-biotin exchange, coimmunoprecipitation, and biotinylation assays were employed.
• Behavioral and electrophysiological methods were used in cultured hippocampal neurons and fear-conditioned rats.
• Inhibition of palmitoyl acyl transferases and knockdown/inhibition of acyl-protein thioesterase 1 (APT1) were performed.

Main Results:

• Palmitoylation levels, PSD-95 and glutamate receptor palmitoylation, PSD-95 localization, AMPAR surface expression, and synaptic strength were enhanced by TTX and reversed by palmitoylation inhibitors.
• APT1-mediated depalmitoylation was found to be involved in PSD-95 palmitoylation and glutamatergic synaptic transmission.
• Knockdown or inhibition of APT1 increased AMPAR-mediated synaptic strength, palmitoylation levels, and PSD-95/AMPAR expression; palmitoylation is essential for synaptic strengthening and fear memory.

Conclusions:

• Palmitoylation and APT1-mediated depalmitoylation critically regulate glutamatergic synaptic plasticity.
• Palmitoylation cycling is implicated in fear conditioning-induced synaptic strengthening and fear memory formation.
• These processes represent potential therapeutic targets for learning and memory-associated disorders.