Abstract
Synapses are the basic units of information transmission, processing and integration in the nervous system. Dysfunction of the synaptic development has been recognized as one of the main reasons for mental dementia and psychiatric diseases such as Alzheimer’s disease and autism. However, the underlying mechanisms of the synapse formation are far from clear. Here we report that phospholipase D1 (PLD1) promotes the development of dendritic spines in hippocampal neurons. We found that overexpressing PLD1 increases both the density and the area of dendritic spines. On the contrary, loss of function of PLD1, including overexpression of the catalytically-inactive PLD1 (PLD1ci) or knocking down PLD1 by siRNAs, leads to reduction in the spine density and the spine area. Moreover, we found that PLD1 promotes the dendritic spine development via regulating the membrane level of N-cadherin. Further studies showed that the regulation of surface N-cadherin by PLD1 is related with the cleavage of N-cadherin by a member of the disintegrin and metalloprotease family-ADAM10. Taking together, our results indicate a positive role of PLD1 in synaptogenesis by inhibiting the ADAM10 mediated N-cadherin cleavage and provide new therapeutic clues for some neurological diseases.
Highlights
With the enrichment of different kinds of receptors for neural transmission, dendritic spines are important parts for information processing and integration[1, 2]
The results showed that compared to the empty vector control, overexpressing Phospholipase D1 (PLD1) in hippocampal neurons induced the growth and maturation of dendritic spines as measured by their density and area (Fig. 1A)
We found that knocking down PLD1 in cultured hippocampal neurons dramatically decreased the spine density and spine area (Fig. 1C)
Summary
With the enrichment of different kinds of receptors for neural transmission, dendritic spines are important parts for information processing and integration[1, 2]. Most of the genes which are highly correlated with psychiatric diseases play important roles in dendritic spine development[6,7,8,9,10,11]. Elucidating the mechanisms of dendritic spine development is crucial for understanding both the assembly of neural connections and the pathology for neurological diseases. Combined with the fact that PLD1-mediated tPA signaling pathway participates hippocampal mossy fiber sprouting[31], we believe that PLD1 may play an important part in neuronal dendritic spine development. We found that PLD1 promotes the dendritic spine development by preventing N-cadherin from being cleaved by ADAM10, suggesting a potential role of PLD1 as an important regulator and a novel therapeutic target in neurological diseases
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