title: Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus.
abstract: Elevations in neuronal cholesterol have been associated with several degenerative diseases. An enhanced excitability and synchronous firing in surviving neurons are among the sequels of neuronal death in these diseases and also in some epileptic syndromes. Here, we attempted to increase neuronal cholesterol levels, using a short hairpin RNA to suppress expression of the enzyme cytochrome P450 family 46, subfamily A, polypeptide 1 gene (CYP46A1). This protein hydroxylates cholesterol and so facilitates transmembrane extrusion. A short hairpin RNA CYP46A1construction coupled to the adeno-associated virus type 5 was injected focally and unilaterally into mouse hippocampus. It was selectively expressed first in neurons of the cornu ammonis (hippocampus) (CA)3a region. Cytoplasmic and membrane cholesterol increased, and the neuronal soma volume increased and then decreased before pyramidal cells died. As CA3a pyramidal cells died, interictal electroencephalographic (EEG) events occurred during exploration and non-rapid eye movement sleep. With time, neuronal death spread to involve pyramidal cells and interneurons of the CA1 region. CA1 neuronal death was correlated with a delayed local expression of phosphorylated tau. Astrocytes were activated throughout the hippocampus and microglial activation was specific to regions of neuronal death. CA1 neuronal death was correlated with distinct aberrant EEG activity. During exploratory behaviour and rapid eye movement sleep, EEG oscillations at 7-10 Hz (theta) could accelerate to 14-21 Hz (beta) waves. They were accompanied by low-amplitude, high-frequency oscillations of peak power at ~300 Hz and a range of 250-350 Hz. Although episodes of EEG acceleration were not correlated with changes in exploratory behaviour, they were followed in some animals by structured seizure-like discharges. These data strengthen links between increased cholesterol, neuronal sclerosis and epileptic behaviour.
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Farah
authors.initials: F
authors.lastname: Chali
authors.affiliation: CNRS URA2210, MIRCen CEA, Fontenay aux Roses, 92265, France.|INSERM U986 94276 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Djelti
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Eugene
authors.affiliation: Departamento de Ingeniería Biomédica, Universidad de los Andes, Bogotá, Colombia.
authors.forename: Mario
authors.initials: M
authors.lastname: Valderrama
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Marquer
authors.affiliation: CNRS URA2210, MIRCen CEA, Fontenay aux Roses, 92265, France.|INSERM U986 94276 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duykaerts
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.affiliation: CNRS URA2210, MIRCen CEA, Fontenay aux Roses, 92265, France.|INSERM U986 94276 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, 47 bd de l'Hôpital, Paris, 75013, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navarro
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016923:Cell Death; D002784:Cholesterol / Q000378:metabolism / Q000633:toxicity*; D000072556:Cholesterol 24-Hydroxylase; D000229:Dependovirus / Q000502:physiology; D004569:Electroencephalography; D004827:Epilepsy / Q000209:etiology / Q000473:pathology*; D005260:Female; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D010766:Phosphorylation; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012598:Sclerosis; D013250:Steroid Hydroxylases / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016875:tau Proteins; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase
keywords: cholesterol; cytochrome P450 family 46 subfamily A; epilepsy; neurodegeneration
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