title: 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.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tapia
authors.forename: Austen
authors.initials: A
authors.lastname: Milnerwood
authors.forename: Aobo
authors.initials: A
authors.lastname: Guo
authors.forename: Fergil
authors.initials: F
authors.lastname: Mills
authors.forename: Eileen
authors.initials: E
authors.lastname: Yoshida
authors.forename: Cristina
authors.initials: C
authors.lastname: Vasuta
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Lynn
authors.initials: L
authors.lastname: Raymond
authors.forename: Max
authors.initials: M
authors.lastname: Cynader
authors.forename: William
authors.initials: W
authors.lastname: Jia
authors.forename: Shernaz X
authors.initials: SX
authors.lastname: Bamji
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C092350:FM 4-64; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D016708:Synaptophysin; D013778:Tetrazolium Salts; D013844:Thiazoles; C413663:fluorescent protein 583; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; C022616:thiazolyl blue; C104722:glutamate receptor ionotropic, AMPA 2