“…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.…”