Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone

AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC n...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2012-02, Vol.73 (3), p.511-522
Main Authors: Liu, Tiemin, Kong, Dong, Shah, Bhavik P., Ye, Chianping, Koda, Shuichi, Saunders, Arpiar, Ding, Jun B., Yang, Zongfang, Sabatini, Bernardo L., Lowell, Bradford B.
Format: Article
Language:English
Subjects:
2-Amino-5-phosphonovalerate - pharmacology
6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology
Age Factors
Agouti-Related Protein - deficiency
Agouti-Related Protein - metabolism
Animals
Body Composition - drug effects
Body Composition - genetics
Brain - cytology
Carrier Proteins - genetics
Dendritic Spines - drug effects
Dendritic Spines - physiology
Eating - drug effects
Eating - physiology
Energy Metabolism - drug effects
Energy Metabolism - genetics
Excitatory Amino Acid Antagonists - pharmacology
Excitatory Postsynaptic Potentials - drug effects
Excitatory Postsynaptic Potentials - genetics
Fasting
Female
Food
GABA Antagonists - pharmacology
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Genetic engineering
Green Fluorescent Proteins - genetics
In Vitro Techniques
Kinases
Male
Membrane Potentials - drug effects
Membrane Potentials - genetics
Mice
Mice, Transgenic
Nerve Tissue Proteins - deficiency
Nerve Tissue Proteins - genetics
Neurons
Neurons - cytology
Neurons - drug effects
Neuropeptide Y - genetics
Patch-Clamp Techniques
Picrotoxin - pharmacology
Pro-Opiomelanocortin - genetics
Proto-Oncogene Proteins c-fos - metabolism
Receptors, N-Methyl-D-Aspartate - deficiency
RNA, Messenger
Rodents
Time Factors
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Summary:AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting. ► NMDARs on AgRP but not POMC neurons regulate feeding and body weight ► AgRP neurons have many dendritic spines; POMC neurons, in contrast, are aspiny ► Fasting activation of AgRP neurons requires NMDARs and increased excitatory tone ► Increased excitatory tone is likely caused by NMDAR-driven dendritic spinogenesis AgRP neurons drive feeding behavior. Liu et al. find that fasting activation of AgRP neurons requires postsynaptic NMDARs, promoting dendritic spinogenesis, likely synaptogenesis, and increasing excitatory tone. Thus, NMDAR-mediated synaptic plasticity is a key regulator of AgRP neurons and feeding behavior.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2011.11.027