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J Neurophysiol. 2015 Mar 15;113(6):1712-26. doi: 10.1152/jn.00419.2014. Epub 2014 Dec 24.

Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPARγ agonism.

Author information

  • 1Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas;
  • 2Department 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.
  • 3Department 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.
  • 4Department 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.

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.

KEYWORDS:

Alzheimer's disease; dentate gyrus; excitability; patch clamp; peroxisome proliferator-activated receptor-γ

PMID:
25540218
PMCID:
PMC4359997
DOI:
10.1152/jn.00419.2014
[PubMed - indexed for MEDLINE]
Free PMC Article
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