title: Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons.
abstract: Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Oettinghaus
authors.affiliation: Division of Neurophysiology, Institute of Physiology, Department of Biomedicine, University of Basel, Basel 4056, Switzerland.
authors.forename: J M
authors.initials: JM
authors.lastname: Schulz
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: L M
authors.initials: LM
authors.lastname: Restelli
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.|Department of Neurosurgery, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Licci
authors.affiliation: Department of Biology, University of Padua, Padua 35121, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Savoia
authors.affiliation: Proteomics Core Facility, Biozentrum, University of Basel, Basel 4056, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Neurobiology Laboratory for Brain and Mental Health, University Psychiatric University Clinics Basel, University of Basel, Basel 4012, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Schmitt
authors.affiliation: Neurobiology Laboratory for Brain and Mental Health, University Psychiatric University Clinics Basel, University of Basel, Basel 4012, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Dulbecco Telethon Institute IRCCS, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Morè
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Hench
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Tolnay
authors.affiliation: Neurobiology Laboratory for Brain and Mental Health, University Psychiatric University Clinics Basel, University of Basel, Basel 4012, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Eckert
authors.affiliation: Dulbecco Telethon Institute IRCCS, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: P
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: Faculty of Biology and Medicine, Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Franken
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ishihara
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan.|Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mihara
authors.affiliation: Division of Neurophysiology, Institute of Physiology, Department of Biomedicine, University of Basel, Basel 4056, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bischofberger
authors.affiliation: Department of Biology, University of Padua, Padua 35121, Italy.|Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, Padua 35129, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Scorrano
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Frank
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001284:Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034281:Dynamins / Q000096:biosynthesis / Q000235:genetics*; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009420:Nervous System / Q000254:growth & development* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; C486391:Dnm1l protein, mouse; D034281:Dynamins