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.

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…This section refers to data that were previously collected (Nenov et al, 2015), then additional set of analyses were done seeking functional changes attributing to AIS reorganization and presented in this study. Slice preparation and whole-cell patch-clamp experiments were performed as described previously (Nenov et al, 2015).…”

“…Slice preparation and whole-cell patch-clamp experiments were performed as described previously (Nenov et al, 2015). Briefly, acute hippocampal slices were sectioned from 9-mo-old wild-type littermate control and Tg2576 mice, treated with RSG.…”

“…Using confocal microscopy and image quantification, we show that the Tg2576 phenotype is characterized by a reduction in PanNav and the PanNav:FGF14 ratio at the AIS, which is reversed by treatment with RSG. Analysis of previously published electrophysiological data, which established a mechanistic link between cognitive improvement by thiazolidinediones and neuronal excitability in an AD mouse model (Nenov et al, 2015), provides correlative findings to the imaging studies. In addition, we show that phosphorylation of FGF14 at S226 by GSK–3 occurs in vitro, while the phosphosilent mutant FGF14 S226A reduced complex formation with Nav1.6.…”

“…Supporting this link, the class of insulin-sensitizing drug known as the thiazolidinediones, which includes rosiglitazone (RSG) and pioglitazone (PIO), and are potent and selective agonist of the peroxisome proliferator-activated receptor gamma (PPARγ), has shown efficacy in patients with MCI (Mild Cognitive Impairment) and concomitant insulin resistance (Risner et al, 2006; Harrington et al, 2007; Watson et al, 2005; Gad et al, 2015; Sato et al, 2011; Perez & Quintanilla, 2015). Likewise, RSG treatment rescues hippocampus-dependent cognitive function in the Tg2576 AD mouse model (Rodriguez-Rivera et al, 2011; Denner et al, 2012) by a mechanism that involves normalized intrinsic excitability and synaptic function of granule neurons in the dentate gyrus (DG), a critical location for new memory formation (Nenov et al, 2015). Dysregulation of the ERK-MAPK signaling pathway that subserves hippocampus-dependent cognition (Denner et al, 2012; Ahi et al, 2004; Atkins et al, 1998; Sweatt, 2004; McGaugh, 2000; Jahrling et al, 2014), the presynaptic VAMP-2 glutamate release machinery (Nenov et al, 2014), and voltage-gated ion channels (Nenov et al, 2015) may mediate the effect of RSG treatment on granule neuron function, but details of how PPARγ–agonism affects excitability in ion channel complexes are lacking.…”

“…Likewise, RSG treatment rescues hippocampus-dependent cognitive function in the Tg2576 AD mouse model (Rodriguez-Rivera et al, 2011; Denner et al, 2012) by a mechanism that involves normalized intrinsic excitability and synaptic function of granule neurons in the dentate gyrus (DG), a critical location for new memory formation (Nenov et al, 2015). Dysregulation of the ERK-MAPK signaling pathway that subserves hippocampus-dependent cognition (Denner et al, 2012; Ahi et al, 2004; Atkins et al, 1998; Sweatt, 2004; McGaugh, 2000; Jahrling et al, 2014), the presynaptic VAMP-2 glutamate release machinery (Nenov et al, 2014), and voltage-gated ion channels (Nenov et al, 2015) may mediate the effect of RSG treatment on granule neuron function, but details of how PPARγ–agonism affects excitability in ion channel complexes are lacking. Because voltage-gated ion channels are the fundamental unit of excitability in the neuron, investigating how RSG treatment affects ion channel proteins may identify critical nodes in downstream pathways of Aβ pathology and provide useful information for therapeutic strategies (Rusinova et al, 2011; Imbrici et al, 2016; Catterall, 2012).…”