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Prosapip1 (encoded by the Lzts3 gene) in the dorsal hippocampus mediates synaptic protein composition, long-term potentiation, and spatial memory.

Zachary W Hoisington | Himanshu Gangal | Khanhky Phamluong | Chhavi Shukla | Jeffrey J Moffat | Alexandra Salvi | Gregg Homanics | Jun Wang | Yann Ehinger | Dorit Ron
eLife | 2025

 Prosapip1 is a brain-specific protein, encoded by Lzts3, localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However, nothing is known about the role of Prosapip1 in vivo. To examine this, we utilized the Cre-loxP system to develop a Prosapip1 neuronal knockout mouse. We found that Prosapip1 controls the synaptic localization of its binding partner SPAR, along with PSD-95 and the GluN2B subunit of the NMDA receptor (NMDAR) in the dorsal hippocampus (dHP). We next sought to identify the potential contribution of Prosapip1 to the activity and function of the NMDAR and found that Prosapip1 plays an important role in NMDAR-mediated transmission and long-term potentiation (LTP) in the CA1 region of the dHP. As LTP is the cellular hallmark of learning and memory, we examined the consequences of neuronal knockout of Prosapip1 on dHP-dependent memory. We found that global or dHP-specific neuronal knockout of Prosapip1 caused a deficit in learning and memor,y whereas developmental, locomotor, and anxiety phenotypes were normal. Taken together, Prosapip1 in the dHP promotes the proper localization of synaptic proteins which, in turn, facilitates LTP driving recognition, social, and spatial learning and memory.

Pubmed ID: 41295083

Associated grants

  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA027682
  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA027474
  • Agency: NIGMS NIH HHS, United States
    Id: GM007175
  • Agency: NIAAA NIH HHS, United States
    Id: AA020889
  • Agency: NIAAA NIH HHS, United States
    Id: U01 AA020889
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007175
  • Agency: NIAAA NIH HHS, United States
    Id: AA027474
  • Agency: NIAAA NIH HHS, United States
    Id: AA027682

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