Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses

Abstract

Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.

Activity-dependent secretion of progranulin from synapses

“…6E,F). These results are consistent with our previous findings demonstrating a significant decrease in synapse density and increase in the size of Vglut-and synaptophysin-immunopositive puncta and the number of synaptic vesicles per synapse following PGRN knockdown (Tapia et al, 2011).…”

“…Progranulin is a secreted protein exhibiting neurotrophic functions including regulation of neuronal survival and neurite outgrowth (Ryan et al, 2009;Tapia et al, 2011;Van Damme et al, 2008). We next determined the relationship between PGRN and brain-derived neurotrophic factor (BDNF), another secreted trophic factor expressed in both axons and dendrites (Adachi et al, 2005;Jakawich et al, 2010;Matsuda et al, 2009), but see also Dieni et al (Dieni et al, 2012).…”

“…Previous work from our lab has demonstrated that knocking down PGRN levels in rat primary hippocampal cultures reduces neuronal arborization and the density of synapses, but enhances the size of presynaptic compartments and the frequency of mini excitatory postsynaptic currents (mEPSCs) of the remaining synapses (Tapia et al, 2011). In addition, PGRN knockout mice display altered synaptic connectivity, impaired synaptic plasticity and abnormal neuronal morphology (Petkau et al, 2012).…”

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

“…After thresholding, the VGLUT1 clusters were dilated one point in ImageJ to increase the probability of counting as colocalized VGLUT1 and YFP-GluN2B clusters that were opposed but not overlapping. Colocalization was calculated using an ImageJ colocalization plugin (http://rsb.info.nih.gov/ij/plugins/colocalization.html) as in Tapia et al (2011).…”

P1‐196: Frontotemporal Dementia and Psychiatric Illness: Emerging Clinical and Biological Links in Gene Carriers

“…While the mechanisms by which FTDassociated mutations cause disease are still being determined, it is clear that they disrupt cell function in ways that can cause subtle structural and functional changes. [37][38][39][40][41][42][43] Mutationbased animal models of FTD have demonstrated subtle morphological changes in neurons, such as decreased synaptic density, altered spine morphology, and altered synaptic vesicle content, 40,41,44,45 as well as changes in physiological functions, such as excitatory postsynaptic potentials 41,44 and long-term potentiation. 45 These findings can be demonstrated in mice with behavioral abnormalities, such as anxiety and altered social interaction, months before neuropathological abnormalities develop.…”