%0 Journal Article %A Francesca Longhena %A Michela Zaltieri %A Jessica Grigoletto %A Gaia Faustini %A Luca La Via %A Roberta Ghidoni %A Luisa Benussi %A Cristina Missale %A PierFranco Spano %A Arianna Bellucci %T Depletion of progranulin reduces GluN2B-containing NMDA receptor density, tau phosphorylation and dendritic arborization in mouse primary cortical neurons %D 2017 %R 10.1124/jpet.117.242164 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.117.242164 %X Loss-of-function mutations in the progranulin (PGRN) gene are a common cause of familial frontotemporal lobar degeneration (FTLD). This an age-related neurodegenerative disorder characterized by brain atrophy in the frontal and temporal lobes and with typical symptoms such as cognitive and memory impairment, profound behavioral abnormalities and personality changes, that are thought to be related to connectome dysfunctions. Recently, PGRN reduction has been found to induce a behavioural phenotype reminiscent of FTLD symptoms in mice by affecting neuron spine density and morphology, suggesting that the protein can influence neuronal structural plasticity. Here, we evaluated whether a partial haploinsufficiency-like PGRN depletion, achieved by using RNA interference in primary mouse cortical neurons, could modulate GluN2B-containing N-methyl-D-aspartate (NMDA) receptors and tau phosphorylation, that are crucially involved in the regulation of the structural plasticity of these cells. In addition, we studied the effect of PGRN decrease on neuronal cell arborization both in the presence and absence of GluN2B-containing NMDA receptor stimulation.We found that PGRN decline diminished GluN2B-containing NMDA receptor levels and density as well as NMDA-dependent tau phosphorylation. These alterations were accompanied by a marked drop of neuronal arborization, that was prevented by an acute GluN2B-containing NMDA receptor stimulation. Our findings support that PGRN decrease, resulting from pathogenic mutations, might compromise the trophism of cortical neurons by affecting GluN2B-contaning NMDA receptors. These mechanisms might be implicated in the pathogenesis of FTLD. %U https://jpet.aspetjournals.org/content/jpet/early/2017/09/12/jpet.117.242164.full.pdf