PRG-4 (LPPR2) is important for correct protein targeting towards synaptic structures affecting memory and learning

Plasticity-related genes (PRGs/LPPRs)) belong to a novel subgroup of the lipid phosphate phosphatases family and play a critical role in modulating lysophosphatidic acid signaling in the central nervous system. One characteristic of these proteins is that they tend to come in different combinations and functionally cooperate (Yu, 2015). Here, we sought to explore the role of the poorly characterized PRG-4 comparing wild-type and PRG-4 knockout (PRG4-/-) mice by biochemical and cell biological means, and behavioral tests. Lack of PRG-4 resulted in significantly decreased PRG-1/LPPR4 levels in the whole brain and in the postsynaptic density of glutamatergic cortical synapses while PRG-4 was absent in synaptic structures in PRG-1 knockout mice. Moreover, in hippocampal neurons of PRG4-/- mice, PRG-1 was found to be located in the cell body, but was largely absent in dendrites and spines in contrast to its distribution in wild-type neurons. Employing life cell imaging of newly synthesized PRG1-GFP, we show that PRG-1’s transportation into dendrites and spines is compromised in PRG4-/- neurons, possibly due to impaired export from the endoplasmic reticulum. PRG-1’s mislocalization in PRG4-/- primary hippocampal neurons was rescued by the expression of PRG-4. PRG4-/- mice display poor learning in a Morris water maze test, indicating that PRG-4 is necessary for PRG-1’s subcellular transportation and function. Taken together, our data reveal that PRG-1 and PRG-4 mutually interact in vivo and that PRG-4 is critical for the correct protein targeting into dendrites and spines and plays an important role in proper memory formation and learning.