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 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.
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Tiemin
T
Liu
Dong
D
Kong
Bhavik P
BP
Shah
Chianping
C
Ye
Shuichi
S
Koda
Arpiar
A
Saunders
Jun B
JB
Ding
Zongfang
Z
Yang
Bernardo L
BL
Sabatini
Bradford B
BB
Lowell
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000367:Age Factors; D054369:Agouti-Related Protein / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005215:Fasting; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009478:Neuropeptide Y / Q000235:genetics; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency; D013997:Time Factors
D015763:2-Amino-5-phosphonovalerate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D054369:Agouti-Related Protein; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D010852:Picrotoxin; D011333:Pro-Opiomelanocortin; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C515199:Agrp protein, mouse; C121673:Gprin1 protein, mouse