PMID- 36095217
OWN - NLM
STAT- MEDLINE
DCOM- 20220914
LR  - 20230313
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 38
DP  - 2022 Sep 20
TI  - Active forgetting requires Sickie function in a dedicated dopamine circuit in 
      Drosophila.
PG  - e2204229119
LID - 10.1073/pnas.2204229119 [doi]
LID - e2204229119
AB  - Forgetting is an essential component of the brain's memory management system, 
      providing a balance to memory formation processes by removing unused or unwanted 
      memories, or by suppressing their expression. However, the molecular, cellular, 
      and circuit mechanisms underlying forgetting are poorly understood. Here we show 
      that the memory suppressor gene, sickie, functions in a single dopamine neuron 
      (DAn) by supporting the process of active forgetting in Drosophila. RNAi 
      knockdown (KD) of sickie impairs forgetting by reducing the Ca(2+) influx and DA 
      release from the DAn that promotes forgetting. Coimmunoprecipitation/mass 
      spectrometry analyses identified cytoskeletal and presynaptic active zone (AZ) 
      proteins as candidates that physically interact with Sickie, and a focused RNAi 
      screen of the candidates showed that Bruchpilot (Brp)-a presynaptic AZ protein 
      that regulates calcium channel clustering and neurotransmitter release-impairs 
      active forgetting like sickie KD. In addition, overexpression of brp rescued the 
      impaired forgetting of sickie KD, providing evidence that they function in the 
      same process. Moreover, we show that sickie KD in the DAn reduces the abundance 
      and size of AZ markers but increases their number, suggesting that Sickie 
      controls DAn activity for forgetting by modulating the presynaptic AZ structure. 
      Our results identify a molecular and circuit mechanism for normal levels of 
      active forgetting and reveal a surprising role of Sickie in maintaining 
      presynaptic AZ structure for neurotransmitter release.
FAU - Zhang, Xiaofan
AU  - Zhang X
AD  - Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 
      33458.
FAU - Sabandal, John Martin
AU  - Sabandal JM
AD  - Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 
      33458.
FAU - Tsaprailis, George
AU  - Tsaprailis G
AUID- ORCID: 0000-0003-1239-2358
AD  - Proteomics Core, UF Scripps Biomedical, Jupiter, FL 33458.
FAU - Davis, Ronald L
AU  - Davis RL
AD  - Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 
      33458.
AD  - Department of Neuroscience, UF Scripps Biomedical, Jupiter, FL 33458.
LA  - eng
GR  - R35 NS097224/NS/NINDS NIH HHS/United States
GR  - R37 NS019904/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220912
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Drosophila Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (sick protein, Drosophila)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - *Dopamine/metabolism
MH  - *Drosophila Proteins/genetics/physiology
MH  - *Drosophila melanogaster/genetics
MH  - *Memory
MH  - *Nerve Tissue Proteins/genetics/physiology
MH  - Presynaptic Terminals/physiology
MH  - Synaptic Transmission
PMC - PMC9499536
OTO - NOTNLM
OT  - Bruchpilot
OT  - Drosophila
OT  - Sickie
OT  - active forgetting
OT  - dopamine
COIS- The authors declare no competing interest.
EDAT- 2022/09/13 06:00
MHDA- 2022/09/15 06:00
PMCR- 2023/03/12
CRDT- 2022/09/12 15:23
PHST- 2022/09/12 15:23 [entrez]
PHST- 2022/09/13 06:00 [pubmed]
PHST- 2022/09/15 06:00 [medline]
PHST- 2023/03/12 00:00 [pmc-release]
AID - 202204229 [pii]
AID - 10.1073/pnas.2204229119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2204229119. doi: 
      10.1073/pnas.2204229119. Epub 2022 Sep 12.