title: Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry.
abstract: Membrane/lipid rafts (MLR) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis of mevalonic, a precursor to cholesterol via the mevalonate pathway. Because there has been controversy over the effects of statins on neuronal and cognitive function, we investigated the impact of long-term atorvastatin treatment (5mg/kg/d for 7 months by oral gavage) on behavior, cognition, and brain biochemistry in mice. We hypothesized that long-term statin treatment would alter lipid rafts and cognitive function. Atorvastatin treatment resulted in behavioral deficits as measured in paradigms for basic exploration (open field activity) and cognitive function (Barnes maze, startle response) without impairment in global motor function (Rotor Rod). Furthermore, significant changes in MLR-associated proteins (syntaxin-1α and synaptophysin) and a global change of post-synaptic density protein-95 (PSD95) were observed. The observed decreases in the MLR-localized pre-synaptic vesicle proteins syntaxin-1α and synaptophysin suggest a molecular mechanism for the statin-associated impairment of cognitive function that was observed and that has been suggested by the clinical literature.
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.affiliation: Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Cui
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92092, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Godoy
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92092, USA.
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Risbrough
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Drummond
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: azemljicharpf@ucsd.edu.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Zemljic-Harpf
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: bhead@ucsd.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D051528:Guanylate Kinases / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D013997:Time Factors
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; C494214:Stx1a protein, mouse; D016708:Synaptophysin; D050827:Syntaxin 1; C569015:Syp protein, mouse; D000069059:Atorvastatin; D051528:Guanylate Kinases
keywords: Atorvastatin; Brain; Cholesterol; Hypercholesterolemia; Lipid; Pharmacology