, 1999), the upregulation of Kir6.2 in POMC neurons in older mice is likely to increase the expression

of KATP channels, leading to hyperpolarization and neuronal silencing (Figure 2). Moreover, constitutive mTOR activation that results in excessive protein translation www.selleckchem.com/GSK-3.html could lead to ER stress (Reiling and Sabatini, 2006), and ER stress may silence brain endothelial cells by increasing the activity of Kir2.1 channels (Kito et al., 2011). Interestingly, multi-unit recording in the hypothalamic suprachiasmatic nucleus of aging rats has revealed a reduction in the amplitude of the electrical rhythm (Nakamura et al., 2011). The aging process has also been shown to modulate ion channels such as the expression of Kv1.1 and Kv1.2 in Purkinje neurons

(Zhang et al., 2010). It would be of interest to test in future Selleck Panobinostat studies whether the age-dependent elevation of mTOR signaling causes ER stress in POMC neurons, and if ER stress or other aspects of mTOR signaling would unleash KATP channel trafficking or in some other ways increase KATP channel density, and ultimately reduce POMC neuron excitability. We have shown that inhibiting mTOR by infusing rapamycin can promote POMC neuronal projections to their target region, the PVN (Figure 7). POMC neurons exert their anorexigenic effects on neurons expressing melanocortin 4 receptor (MC4R), a mandatory receptor for mediating the α-MSH effect in vivo (Vaisse et al., 1998). The expansion of POMC neuronal projection to the PVN with MC4R expression is likely one of the mechanisms for rapamycin to reduce midlife obesity. Multiple studies have revealed the impact of mTOR signaling on neuronal morphology. For example, rapamycin injection restores axon projection in Pomc-cre;Tsc1-f/f mice ( Mori 4-Aminobutyrate aminotransferase et al., 2009). Other studies have shown that the AKT-TSC-mTOR pathway plays a pivotal role in axon/dendrite polarity, axon/dendrite growth and projection ( Choi et al., 2008). Activating

mTOR by the AKT-TSC pathway upregulates SAD kinase, a kinase that determines the fate of neurite development by phosphorylating tau protein ( Kishi et al., 2005; Wildonger et al., 2008). In the visual system of fruit flies, increased TSC-TOR signaling cell autonomously affects photoreceptor axon guidance ( Knox et al., 2007). Recent study also has shown that deleting the autophagy gene 7 (Atg7) in POMC neurons reduces neurite projection to the PVN ( Coupé and Bouret, 2012). Interestingly, Atg7 is inhibited by mTOR ( Wyttenbach et al., 2008). Hence, the elevated mTOR signaling in POMC neurons of aged mice may suppress Atg7 and reduce neurite projection. Another study has found that deleting the LKB1 kinase, another suppressor of mTOR, in POMC neurons also reduces POMC neuronal projections to the PVN ( Claret et al., 2011).