title: Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPARγ agonism.
abstract: Early cognitive impairment in Alzheimer's disease (AD) correlates with medial temporal lobe dysfunction, including two areas essential for memory formation: the entorhinal cortex and dentate gyrus (DG). In the Tg2576 animal model for AD amyloidosis, activation of the peroxisome proliferator-activated receptor-gamma (PPARγ) with rosiglitazone (RSG) ameliorates hippocampus-dependent cognitive impairment and restores aberrant synaptic activity at the entorhinal cortex to DG granule neuron inputs. It is unknown, however, whether intrinsic firing properties of DG granule neurons in these animals are affected by amyloid-β pathology and if they are sensitive to RSG treatment. Here, we report that granule neurons from 9-mo-old wild-type and Tg2576 animals can be segregated into two cell types with distinct firing properties and input resistance that correlate with less mature type I and more mature type II neurons. The DG type I cell population was greater than type II in wild-type littermates. In the Tg2576 animals, the type I and type II cell populations were nearly equal but could be restored to wild-type levels through cognitive enhancement with RSG. Furthermore, Tg2576 cell firing frequency and spike after depolarization were decreased in type I and increased in type II cells, both of which could also be restored to wild-type levels upon RSG treatment. That these parameters were restored by PPARγ activation emphasizes the therapeutic value of RSG against early AD cognitive impairment.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas;
authors.forename: Miroslav N
authors.initials: MN
authors.lastname: Nenov
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas;
authors.forename: Filippo
authors.identifier: http://orcid.org/0000-0003-2778-0943
authors.initials: F
authors.lastname: Tempia
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Larry
authors.initials: L
authors.lastname: Denner
authors.affiliation: Department of Neurology, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, Texas felaezza@utmb.edu.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Laezza
mesh_terms: D000200:Action Potentials; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D003071:Cognition; D018728:Entorhinal Cortex / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Alzheimer's disease; dentate gyrus; excitability; patch clamp; peroxisome proliferator-activated receptor-γ