title: Cognitive enhancing treatment with a PPARγ agonist normalizes dentate granule cell presynaptic function in Tg2576 APP mice.
abstract: Hippocampal network hyperexcitability is considered an early indicator of Alzheimer's disease (AD) memory impairment. Some AD mouse models exhibit similar network phenotypes. In this study we focused on dentate gyrus (DG) granule cell spontaneous and evoked properties in 9-month-old Tg2576 mice that model AD amyloidosis and cognitive deficits. Using whole-cell patch-clamp recordings, we found that Tg2576 DG granule cells exhibited spontaneous EPSCs that were higher in frequency but not amplitude compared with wild-type mice, suggesting hyperactivity of DG granule cells via a presynaptic mechanism. Further support of a presynaptic mechanism was revealed by increased I-O relationships and probability of release in Tg2576 DG granule cells. Since we and others have shown that activation of the peroxisome proliferator-activated receptor gamma (PPARγ) axis improves hippocampal cognition in mouse models for AD as well as benefitting memory performance in some humans with early AD, we investigated how PPARγ agonism affected synaptic activity in Tg2576 DG. We found that PPARγ agonism normalized the I-O relationship of evoked EPSCs, frequency of spontaneous EPSCs, and probability of release that, in turn, correlated with selective expression of DG proteins essential for presynaptic SNARE function that are altered in patients with AD. These findings provide evidence that DG principal cells may contribute to early AD hippocampal network hyperexcitability via a presynaptic mechanism, and that hippocampal cognitive enhancement via PPARγ activation occurs through regulation of presynaptic vesicular proteins critical for proper glutamatergic neurotransmitter release, synaptic transmission, and short-term plasticity.
authors.affiliation: Department of Neurology, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, Department of Internal Medicine, Preventive Medicine and Community Health, Mitchell Center for Neurodegenerative Diseases, Center for Addiction Research, Center for Biomedical Engineering, and Sealy Center for Molecular Medicine, Institute for Translational Science, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Miroslav N
authors.initials: MN
authors.lastname: Nenov
authors.forename: Fernanda
authors.initials: F
authors.lastname: Laezza
authors.forename: Sigmund J
authors.initials: SJ
authors.lastname: Haidacher
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rovshan G
authors.initials: RG
authors.lastname: Sadygov
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Starkey
authors.forename: Heidi
authors.initials: H
authors.lastname: Spratt
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
authors.forename: Larry
authors.initials: L
authors.lastname: Denner
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D060066:Protein Interaction Maps / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018697:Nootropic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Alzheimer's; SNARE proteins; animal model; mass spectrometry; patch clamp; synaptic plasticity