title: Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.
abstract: Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. Electronic address: alfredo.ramos@ubc.ca.
authors.forename: A
authors.initials: A
authors.lastname: Ramos-Miguel
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada.
authors.forename: W G
authors.initials: WG
authors.lastname: Honer
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Anesthesiology, Pharmacology, & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: H N
authors.initials: HN
authors.lastname: Boyda
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Kochi Prefectural Aki General Hospital, 1-32 Hoeicho Aki, Kochi Prefecture 784-0027, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sawada
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada.
authors.forename: C L
authors.initials: CL
authors.lastname: Beasley
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Procyshyn
authors.affiliation: BC Mental Health & Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Anesthesiology, Pharmacology, & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Barr
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001569:Benzodiazepines / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005081:Exercise Therapy / Q000379:methods*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008659:Metabolic Diseases / Q000139:chemically induced / Q000473:pathology* / Q000534:rehabilitation*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000077152:Olanzapine; D050683:R-SNARE Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D001569:Benzodiazepines; D000077152:Olanzapine
keywords: ELISA; SNARE; atypical antipsychotics; confocal microscopy; inhibitory terminals; metabolic side-effects