Active forgetting requires Sickie function in a dedicated dopamine circuit in Drosophila

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Forgetting is vital for memory management, balancing memory formation by removing or suppressing unwanted memories.
• The molecular and cellular mechanisms driving active forgetting remain largely unknown.
• Understanding forgetting mechanisms is key to addressing memory-related disorders.

Purpose of the Study:

• To elucidate the molecular and circuit mechanisms of active forgetting in Drosophila.
• To identify genes and neuronal pathways involved in the forgetting process.
• To investigate the role of the memory suppressor gene, sickie, in active forgetting.

Main Methods:

• RNA interference (RNAi) knockdown of the sickie gene in Drosophila.
• Calcium (Ca2+) imaging and dopamine (DA) release measurements in dopamine neurons (DAn).
• Coimmunoprecipitation/mass spectrometry to identify interacting proteins.
• Focused RNAi screen of candidate proteins, including Bruchpilot (Brp).

Main Results:

• Sickie knockdown impairs active forgetting by reducing Ca2+ influx and DA release from DAn.
• Sickie interacts with cytoskeletal and presynaptic active zone (AZ) proteins, notably Bruchpilot (Brp).
• Bruchpilot (Brp) is essential for active forgetting; its overexpression rescues sickie knockdown-induced forgetting deficits.
• Sickie modulates presynaptic AZ structure, affecting AZ marker abundance, size, and number, which is critical for neurotransmitter release.

Conclusions:

• Sickie plays a critical role in active forgetting by regulating dopamine neuron (DAn) function.
• Sickie maintains presynaptic active zone (AZ) structure, essential for proper neurotransmitter release and forgetting.
• This study reveals a novel molecular and circuit mechanism underlying active forgetting and the function of Sickie in memory management.