title: Synaptic dysfunction in progranulin-deficient mice.
abstract: Progranulin haploinsufficiency is a common cause of familial frontotemporal dementia (FTD), but the role of progranulin in the brain is poorly understood. To investigate the role of murine progranulin (Grn) in the CNS in vivo, we generated mice targeted at the progranulin locus (Grn) using a gene-trap vector. Constitutive progranulin knockout mice (GrnKO) show moderate abnormalities in anxiety-related behaviors, social interactions, motor coordination, and novel object recognition at 8months of age, many of which differ between males and females. Analysis of synaptic transmission in 10-12 month old GrnKO male mice indicates altered synaptic connectivity and impaired synaptic plasticity. Additionally, apical dendrites in pyramidal cells in the CA1 region of the hippocampus in GrnKO males display an altered morphology and have significantly decreased spine density compared to wild-type (WT) mice. The observed changes in behavior, synaptic transmission, and neuronal morphology in GrnKO mice occur prior to neuropathological abnormalities, most of which are apparent at 18 but not at 8 months of age. We conclude that progranulin deficiency leads to reduced synaptic connectivity and impaired plasticity, which may contribute to FTD pathology in human patients.
authors: Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
authors: Terri L
authors: TL
authors: Petkau
authors: Scott J
authors: SJ
authors: Neal
authors: Austen
authors: A
authors: Milnerwood
authors: Ada
authors: A
authors: Mew
authors: Austin M
authors: AM
authors: Hill
authors: Paul
authors: P
authors: Orban
authors: Jenny
authors: J
authors: Gregg
authors: Ge
authors: G
authors: Lu
authors: Howard H
authors: HH
authors: Feldman
authors: Ian R A
authors: IR
authors: Mackenzie
authors: Lynn A
authors: LA
authors: Raymond
authors: Blair R
authors: BR
authors: Leavitt
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000077155:Granulins; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018408:Patch-Clamp Techniques; D000077153:Progranulins; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins