This then raises the distinct possibility that presynpatic release of glutamate, which then engages postsynaptic NMDARs on AgRP neurons, somehow

initiates the spinogenesis. Neratinib purchase Consistent with this, previous studies have found that dendritic spinogenesis occurs in response to evoked synaptic glutamate release (Engert and Bonhoeffer, 1999 and Maletic-Savatic et al., 1999) and also, very rapidly, following focal glutamate uncaging onto dendritc shafts (Kwon and Sabatini, 2011). As was true with fasting, these studies similarly found a requirement for NMDARs. Combined, these observations suggest that glutamatergic afferents to AgRP neurons are very likely to play important roles in activating AgRP neurons—in promoting spinogenesis via release of glutamate that then engages NMDARs on AgRP neurons, in providing presynaptic partners for the new dendritic spines and, finally, in providing sustained activation of the nascent synapses. The marked effects caused by removing NMDARs from AgRP

neurons reviewed above, in combination with the presence of dendritic spines on AgRP neurons but not on nearby POMC neurons, strongly suggests that glutamatergic neurotransmission, and its regulation via NMDARs, along with signaling events that are confined within dendritic spines, play key roles in regulating the activity of AgRP neurons. Dendritic spines, and the signaling within, serve Anti-diabetic Compound Library research buy three major functions, and each of these has important Levetiracetam implications for mechanisms regulating AgRP neurons and feeding behavior. First, spines are the sites where excitatory afferents are received. Given that AgRP neurons drive feeding behavior (Aponte et al., 2011 and Krashes et al., 2011), these excitatory afferents must, by extension, be key, but presently unknown, drivers of food intake. Identifying these

excitatory afferents should shed new light on neural circuits regulating feeding. Second, NMDARs/spines are mediators of plasticity (i.e., changes in strength of glutamatergic transmission). Given this, it is likely that mechanisms of plasticity, including long term potentiation, long term depression, and dendritic spinogenesis (Collingridge et al., 2010, Engert and Bonhoeffer, 1999, Kessels and Malinow, 2009, Kwon and Sabatini, 2011, Malenka and Nicoll, 1999 and Maletic-Savatic et al., 1999), play important roles in controlling feeding behavior. Third, and of special relevance to hypothalamic neurons, dendritic spines serve as communication hubs where other “inputs” are integrated for the purpose of acutely and chronically modulating glutamatergic transmission. Notable examples of this include dopaminergic and cholinergic modulation, respectively, of glutamatergic transmission in the striatum (Kreitzer and Malenka, 2008) and hippocampus (Buchanan et al., 2010 and Giessel and Sabatini, 2010).