Skip to main content
SpringerLink
Log in

Synaptic Regulation of Metabolism

  • Chapter
  • First Online:
Neural Regulation of Metabolism

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1090))

Abstract

Neurons in the brain, particularly those in the hypothalamus, are essential for the maintenance of whole-body metabolic homeostasis. Dysfunctions or dysregulations of them can result in various metabolic diseases, including eating disorders, obesity, and diabetes. In addition to hormonal and peptidergic regulation, accumulating evidence has shown that these neurons are subject to synaptic regulation, which has been largely overlooked. In this chapter, we focus on synaptic neurotransmission of hypothalamic neurons and summarize current knowledge of synaptic plasticity in the maintenance of energy balance. Synaptic modulation engaged by circulating hormones is also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abizaid A, Liu Z-W, Andrews ZB, Shanabrough M, Borok E, Elsworth JD et al (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116(12):3229–3239

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Anikeeva P, Andalman AS, Witten I, Warden M, Goshen I, Grosenick L et al (2012) Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat Neurosci 15(1):163–170

    CAS  Google Scholar 

  3. Atasoy D, Aponte Y, Su HH, Sternson SM (2008) A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J Neurosci 28(28):7025–7030

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488(7410):172–177

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Auer TO, Duroure K, De Cian A, Concordet J-P, Del Bene F (2014) Highly efficient CRISPR/Cas9-mediated knock-in in zebrafish by homology-independent DNA repair. Genome Res 24(1):142–153

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Baldwin B, Ebenezer I, De La Riva C (1990) Effects of intracerebroventricular injection of muscimol or GABA on operant feeding in pigs. Physiol Behav 48(3):417–421

    CAS  PubMed  Google Scholar 

  7. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V et al (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42(6):983–991

    CAS  PubMed  Google Scholar 

  8. Baskin DG, Breininger JF, Schwartz MW (1999) Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 48(4):828–833

    CAS  PubMed  Google Scholar 

  9. Baver SB, Hope K, Guyot S, Bjørbaek C, Kaczorowski C, O’Connell KM (2014) Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J Neurosci 34(16):5486–5496

    PubMed  PubMed Central  Google Scholar 

  10. Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M et al (2016) Review: Parkinson’s disease: from synaptic loss to connectome dysfunction. Neuropathol Appl Neurobiol 42(1):77–94

    CAS  PubMed  Google Scholar 

  11. Benani A, Hryhorczuk C, Gouazé A, Fioramonti X, Brenachot X, Guissard C et al (2012) Food intake adaptation to dietary fat involves PSA-dependent rewiring of the arcuate melanocortin system in mice. J Neurosci 32(35):11970–11979

    CAS  PubMed  Google Scholar 

  12. Bernstein H-G, Ansorge S, Riederer P, Reiser M, Frölich L, Bogerts B (1999) Insulin-degrading enzyme in the Alzheimer’s disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 263(2):161–164

    CAS  PubMed  Google Scholar 

  13. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z et al (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J 19(12):1680–1682

    CAS  PubMed  Google Scholar 

  14. Bouret SG, Draper SJ, Simerly RB (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304(5667):108–110

    CAS  PubMed  Google Scholar 

  15. Buddhala C, Hsu C-C, Wu J-Y (2009) A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem Int 55(1):9–12

    CAS  PubMed  Google Scholar 

  16. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269(5223):546

    CAS  PubMed  Google Scholar 

  17. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634

    CAS  PubMed  Google Scholar 

  18. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N (2012) Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482(7383):85–88

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cone RD (1999) The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 10(6):211–216

    CAS  PubMed  Google Scholar 

  20. Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA et al (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-ε4 allele. Am J Pathol 162(1):313–319

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL et al (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411(6836):480–484

    CAS  PubMed  Google Scholar 

  22. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL et al (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37(4):649–661

    CAS  PubMed  Google Scholar 

  23. Cui RJ, Li X, Appleyard SM (2011) Ghrelin inhibits visceral afferent activation of catecholamine neurons in the solitary tract nucleus. J Neurosci 31(9):3484–3492

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM (2013) Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494(7436):238–242

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF et al (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9(2):251–259

    CAS  PubMed  Google Scholar 

  26. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B et al (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9(3):381–388

    CAS  PubMed  Google Scholar 

  27. Dietrich MO, Horvath TL (2013) Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci 36(2):65–73

    CAS  PubMed  Google Scholar 

  28. Dombeck DA, Harvey CD, Tian L, Looger LL, Tank DW (2010) Functional imaging of hippocampal place cells at cellular resolution during virtual navigation. Nat Neurosci 13(11):1433–1440

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dow LE, Fisher J, O’Rourke KP, Muley A, Kastenhuber ER, Livshits G et al (2015) Inducible in vivo genome editing with CRISPR-Cas9. Nat Biotechnol 33(4):390–394

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Edell DJ, Toi V, McNeil VM, Clark L (1992) Factors influencing the biocompatibility of insertable silicon microshafts in cerebral cortex. IEEE Trans Biomed Eng 39(6):635–643

    CAS  PubMed  Google Scholar 

  31. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbæk C et al (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23(4):775–786

    CAS  PubMed  Google Scholar 

  32. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, Elmquist JK (2000) Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol 423(2):261–281

    CAS  PubMed  Google Scholar 

  33. Elmquist JK, Elias CF, Saper CB (1999) From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22(2):221–232

    CAS  PubMed  Google Scholar 

  34. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385(6612):165

    CAS  PubMed  Google Scholar 

  35. Farr SA, Banks WA, Morley JE (2006) Effects of leptin on memory processing. Peptides 27(6):1420–1425

    CAS  PubMed  Google Scholar 

  36. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N (2004) Obesity-related leptin regulates Alzheimer’s Aβ. FASEB J 18(15):1870–1878

    CAS  PubMed  Google Scholar 

  37. Figlewicz D, Evans S, Murphy J, Hoen M, Baskin D (2003) Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 964(1):107–115

    CAS  PubMed  Google Scholar 

  38. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185(2):232–240

    PubMed  Google Scholar 

  39. Fremeau RT, Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J et al (2004) Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304(5678):1815–1819

    CAS  PubMed  Google Scholar 

  40. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20(7):2534–2542

    CAS  PubMed  Google Scholar 

  41. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770

    CAS  PubMed  Google Scholar 

  42. Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN et al (2006) Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51(6):811–822

    CAS  PubMed  Google Scholar 

  43. Funahashi H, Yada T, Suzuki R, Shioda S (2003) Distribution, function, and properties of leptin receptors in the brain. Int Rev Cytol 224:1–27

    CAS  PubMed  Google Scholar 

  44. Glaum SR, Hara M, Bindokas VP, Lee CC, Polonsky KS, Bell GI, Miller RJ (1996) Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol Pharmacol 50(2):230–235

    CAS  PubMed  Google Scholar 

  45. Göbel W, Kerr JN, Nimmerjahn A, Helmchen F (2004) Miniaturized two-photon microscope based on a flexible coherent fiber bundle and a gradient-index lens objective. Opt Lett 29(21):2521–2523

    PubMed  Google Scholar 

  46. Gorospe EC, Dave JK (2007) The risk of dementia with increased body mass index. Age Ageing 36(1):23–29

    PubMed  Google Scholar 

  47. Gray CM, Maldonado PE, Wilson M, McNaughton B (1995) Tetrodes markedly improve the reliability and yield of multiple single-unit isolation from multi-unit recordings in cat striate cortex. J Neurosci Methods 63(1):43–54

    CAS  PubMed  Google Scholar 

  48. Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T et al (2005) Agouti-related peptide–expressing neurons are mandatory for feeding. Nat Neurosci 8(10):1289–1291

    CAS  PubMed  Google Scholar 

  49. Guimond D, Diabira D, Porcher C, Bader F, Ferrand N, Zhu M et al (2014) Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus. Front Cell Neurosci 8:235

    PubMed  PubMed Central  Google Scholar 

  50. Gustafson D (2006) Adiposity indices and dementia. Lancet Neurol 5(8):713–720

    PubMed  Google Scholar 

  51. Hahn TM, Breininger JF, Baskin DG, Schwartz MW (1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1(4):271–272

    CAS  PubMed  Google Scholar 

  52. Håkansson M-L, Brown H, Ghilardi N, Skoda RC, Meister B (1998) Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 18(1):559–572

    PubMed  Google Scholar 

  53. Halaas JL, Gajiwala KS, Maffei M, Cohen SL (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223):543

    CAS  PubMed  Google Scholar 

  54. Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, Gersbach CA (2015) Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol 33(5):510–517

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu Z-W, Gao X-B et al (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51(6):801–810

    CAS  PubMed  Google Scholar 

  56. Horvath TL (2006) Synaptic plasticity in energy balance regulation. Obesity 14(S8):228S

    CAS  PubMed  Google Scholar 

  57. Horvath TL, Gao X-B (2005) Input organization and plasticity of hypocretin neurons: possible clues to obesity’s association with insomnia. Cell Metab 1(4):279–286

    CAS  PubMed  Google Scholar 

  58. Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M et al (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci 107(33):14875–14880

    CAS  PubMed  Google Scholar 

  59. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1):131–141

    CAS  PubMed  Google Scholar 

  60. Iadecola C, Davisson RL (2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7(6):476–484

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Incontro S, Asensio CS, Edwards RH, Nicoll RA (2014) Efficient, complete deletion of synaptic proteins using CRISPR. Neuron 83(5):1051–1057

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Jacob TC, Moss SJ, Jurd R (2008) GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 9(5):331–343

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Jao L-E, Wente SR, Chen W (2013) Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc Natl Acad Sci 110(34):13904–13909

    CAS  PubMed  Google Scholar 

  64. Jennings JH, Sparta DR, Stamatakis AM, Ung RL, Pleil KE, Kash TL, Stuber GD (2013) Distinct extended amygdala circuits for divergent motivational states. Nature 496(7444):224–228

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight1. Endocr Rev 20(1):68–100

    CAS  PubMed  Google Scholar 

  66. Kearns NA, Pham H, Tabak B, Genga RM, Silverstein NJ, Garber M, Maehr R (2015) Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat Methods 12:401–403

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim T-i, McCall JG, Jung YH, Huang X, Siuda ER, Li Y et al (2013) Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340(6129):211–216

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kivipelto M, Helkala E-L, Laakso MP, Hanninen T, Hallikainen M, Alhainen K et al (2002) Apolipoprotein E ε4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 137(3):149–155

    CAS  PubMed  Google Scholar 

  69. Komiyama T, Sato TR, O’Connor DH, Zhang Y-X, Huber D, Hooks BM et al (2010) Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice. Nature 464(7292):1182–1186

    CAS  PubMed  Google Scholar 

  70. Konermann S, Brigham MD, Trevino A, Hsu PD, Heidenreich M, Cong L et al (2013) Optical control of mammalian endogenous transcription and epigenetic states. Nature 500(7463):472–476

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C et al (2014) Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517:583–588

    PubMed  PubMed Central  Google Scholar 

  72. Kong D, Tong Q, Ye C, Koda S, Fuller PM, Krashes MJ et al (2012) GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151(3):645–657

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kong D, Dagon Y, Campbell JN, Guo Y, Yang Z, Yi X et al (2016) A postsynaptic AMPK→ p21-activated kinase pathway drives fasting-induced synaptic plasticity in AgRP neurons. Neuron 91(1):25–33

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS et al (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507(7491):238–242

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE (2008) Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity 16(7):1493–1500

    CAS  PubMed  Google Scholar 

  76. Leinninger G, Myers M (2008) LRb signals act within a distributed network of leptin-responsive neurons to mediate leptin action. Acta Physiol 192(1):49–59

    CAS  Google Scholar 

  77. Leshan RL, Louis GW, Jo Y-H, Rhodes CJ, Münzberg H, Myers MG (2009) Direct innervation of GnRH neurons by metabolic-and sexual odorant-sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus. J Neurosci 29(10):3138–3147

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Levin BE, Dunn-Meynell AA (2000) Defense of body weight against chronic caloric restriction in obesity-prone and-resistant rats. Am J Phys Regul Integr Comp Phys 278(1):R231–R237

    CAS  Google Scholar 

  79. Levin BE, Keesey RE (1998) Defense of differing body weight set points in diet-induced obese and resistant rats. Am J Phys Regul Integr Comp Phys 274(2):R412–R419

    CAS  Google Scholar 

  80. Levin BE, Dunn-Meynell AA, Balkan B, Keesey R (1997) Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Phys Regul Integr Comp Phys 273(2):R725–R730

    CAS  Google Scholar 

  81. Levin BE, Dunn-Meynell AA, McMinn JE, Alperovich M, Cunningham-Bussel A, Chua SC (2003) A new obesity-prone, glucose-intolerant rat strain (F. DIO). Am J Phys Regul Integr Comp Phys 285(5):R1184–R1191

    CAS  Google Scholar 

  82. Li X-L, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T (2002) Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 113(3):607–615

    CAS  PubMed  Google Scholar 

  83. Li J-Y, Plomann M, Brundin P (2003) Huntington’s disease: a synaptopathy? Trends Mol Med 9(10):414–420

    CAS  PubMed  Google Scholar 

  84. Liu T, Kong D, Shah BP, Ye C, Koda S, Saunders A et al (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73(3):511–522

    PubMed  PubMed Central  Google Scholar 

  85. Liu J, Conde K, Zhang P, Lilascharoen V, Xu Z, Lim BK et al (2017) Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon-like peptide-1 in the paraventricular hypothalamus. Neuron 96(4):897–909 e895

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518(7538):197–206

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Luchsinger JA, Tang M-X, Shea S, Mayeux R (2004) Hyperinsulinemia and risk of Alzheimer disease. Neurology 63(7):1187–1192

    PubMed  Google Scholar 

  88. Luchsinger JA, Patel B, Tang M-X, Schupf N, Mayeux R (2007) Measures of adiposity and dementia risk in elderly persons. Arch Neurol 64(3):392–398

    PubMed  PubMed Central  Google Scholar 

  89. Luquet S, Perez FA, Hnasko TS, Palmiter RD (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310(5748):683–685

    CAS  PubMed  Google Scholar 

  90. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE et al (2013) RNA-guided human genome engineering via Cas9. Science 339(6121):823–826

    CAS  PubMed  PubMed Central  Google Scholar 

  91. McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389(6653):870–876

    CAS  PubMed  Google Scholar 

  92. Meng F, Han Y, Srisai D, Belakhov V, Farias M, Xu Y et al (2016) New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism. Proc Natl Acad Sci 113(13):3645–3650

    CAS  PubMed  Google Scholar 

  93. Meyer M, Westbrook G, Guthrie P (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurons. Nature 309:261–263

    Google Scholar 

  94. Mietlicki-Baase EG, Ortinski PI, Rupprecht LE, Olivos DR, Alhadeff AL, Pierce RC, Hayes MR (2013) The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors. Am J Physiol Endocrinol Metab 305(11):E1367–E1374

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Miyata S, Nakashima T, Kiyohara T (1994) Structural dynamics of neural plasticity in the supraoptic nucleus of the rat hypothalamus during dehydration and rehydration. Brain Res Bull 34(3):169–175

    CAS  PubMed  Google Scholar 

  96. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257(5074):1248–1251

    CAS  PubMed  Google Scholar 

  97. Münzberg H (2008) Differential leptin access into the brain—a hierarchical organization of hypothalamic leptin target sites? Physiol Behav 94(5):664–669

    PubMed  Google Scholar 

  98. Naylor DE, Liu H, Wasterlain CG (2005) Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 25(34):7724–7733

    CAS  PubMed  Google Scholar 

  99. Nourhashemi F, Deschamps V, Larrieu S, Letenneur L, Dartigues J-F, Barberger-Gateau P (2003) Body mass index and incidence of dementia The PAQUID study. Neurology 60(1):117–119

    CAS  PubMed  Google Scholar 

  100. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurons. Nature 307(5950):462–465

    CAS  PubMed  Google Scholar 

  101. Ollmann MM, Wilson BD, Yang Y-K, Kerns JA, Chen Y, Gantz I, Barsh GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278(5335):135–138

    CAS  PubMed  Google Scholar 

  102. Panza F, D’Introno A, Colacicco A, Basile A, Capurso C, Kehoe P et al (2004) Vascular risk and genetics of sporadic late-onset Alzheimer’s disease. J Neural Transm 111(1):69–89

    CAS  PubMed  Google Scholar 

  103. Panza F, Frisardi V, Capurso C, Imbimbo BP, Vendemiale G, Santamato A et al (2010) Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimers Dis 21(3):691–724

    PubMed  Google Scholar 

  104. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269(5223):540

    CAS  PubMed  Google Scholar 

  105. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X et al (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304(5667):110–115

    CAS  PubMed  Google Scholar 

  106. Polstein LR, Gersbach CA (2015) A light-inducible CRISPR-Cas9 system for control of endogenous gene activation. Nat Chem Biol 11(3):198–200

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Qi Y, Yang Y (2015) Hunger states control the directions of synaptic plasticity via switching cell type-specific subunits of NMDA receptors. J Neurosci 35(38):13171–13182

    CAS  PubMed  Google Scholar 

  108. Qiu C, von Strauss E, Fastbom J, Winblad B, Fratiglioni L (2003) Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol 60(2):223–228

    PubMed  Google Scholar 

  109. Sato TR, Svoboda K (2010) The functional properties of barrel cortex neurons projecting to the primary motor cortex. J Neurosci 30(12):4256–4260

    CAS  PubMed  Google Scholar 

  110. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671

    CAS  PubMed  Google Scholar 

  111. Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK (2009) Leptin targets in the mouse brain. J Comp Neurol 514(5):518–532

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Secher A, Jelsing J, Baquero AF, Hecksher-Sørensen J, Cowley MA, Dalbøge LS et al (2014) The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124(10):4473

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Selkoe D (2001) Alzheimer’s disease is a synaptic failure. J Immunol 166:4278

    Google Scholar 

  114. Shah AN, Davey CF, Whitebirch AC, Miller AC, Moens CB (2015) Rapid reverse genetic screening using CRISPR in zebrafish. Nat Methods 12(6):535–540

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Shanley LJ, Irving AJ, Harvey J (2001) Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci 21(24):RC186

    CAS  PubMed  Google Scholar 

  116. Shen Z, Zhang X, Chai Y, Zhu Z, Yi P, Feng G et al (2014) Conditional knockouts generated by engineered CRISPR-Cas9 endonuclease reveal the roles of coronin in C. elegans neural development. Dev Cell 30(5):625–636

    CAS  PubMed  Google Scholar 

  117. Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 11(5):593–602

    CAS  PubMed  Google Scholar 

  118. Smart JL, Tolle V, Low MJ (2006) Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice. J Clin Investig 116(2):495

    CAS  PubMed  Google Scholar 

  119. Solfrizzi V, Panza F, Colacicco A, D’introno A, Capurso C, Torres F et al (2004) Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 63(10):1882–1891

    CAS  PubMed  Google Scholar 

  120. Solfrizzi V, Capurso C, D’Introno A, Colacicco AM, Santamato A, Ranieri M et al (2008) Lifestyle-related factors in predementia and dementia syndromes. Expert Rev Neurother 8(1):133–158

    PubMed  Google Scholar 

  121. Spanswick D, Smith M, Groppi V, Logan S, Ashford M (1997) Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390(6659):521–525

    CAS  PubMed  Google Scholar 

  122. Stern JE, Armstrong WE (1998) Reorganization of the dendritic trees of oxytocin and vasopressin neurons of the rat supraoptic nucleus during lactation. J Neurosci 18(3):841–853

    CAS  PubMed  Google Scholar 

  123. Stewart R, Masaki K, Xue Q-L, Peila R, Petrovitch H, White LR, Launer LJ (2005) A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia aging study. Arch Neurol 62(1):55–60

    PubMed  Google Scholar 

  124. Straub C, Granger AJ, Saulnier JL, Sabatini BL (2014) CRISPR/Cas9-mediated gene knock-down in post-mitotic neurons. PLoS One 9(8):e105584

    PubMed  PubMed Central  Google Scholar 

  125. Stricker-Krongrad A, Beck B, Nicolas J, Burlet C (1992) Central effects of monosodium glutamate on feeding behavior in adult Long-Evans rats. Pharmacol Biochem Behav 43(3):881–886

    CAS  PubMed  Google Scholar 

  126. Suzanne M (2009) Insulin resistance and Alzheimer’s disease. BMB Rep 42(8):475

    Google Scholar 

  127. Svoboda K, Yasuda R (2006) Principles of two-photon excitation microscopy and its applications to neuroscience. Neuron 50(6):823–839

    CAS  PubMed  Google Scholar 

  128. Swiech L, Heidenreich M, Banerjee A, Habib N, Li Y, Trombetta J et al (2015) In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat Biotechnol 33(1):102–106

    CAS  PubMed  Google Scholar 

  129. Takahashi KA, Cone RD (2005) Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. Endocrinology 146(3):1043–1047

    CAS  PubMed  Google Scholar 

  130. Terunuma M, Xu J, Vithlani M, Sieghart W, Kittler J, Pangalos M et al (2008) Deficits in phosphorylation of GABAA receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci 28(2):376–384

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Theodosis DT, Rougon G, Poulain DA (1991) Retention of embryonic features by an adult neuronal system capable of plasticity: polysialylated neural cell adhesion molecule in the hypothalamo-neurohypophysial system. Proc Natl Acad Sci 88(13):5494–5498

    CAS  PubMed  Google Scholar 

  132. Thompson L, Best P (1990) Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res 509(2):299–308

    CAS  PubMed  Google Scholar 

  133. Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD et al (2007) Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5(5):383–393

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Tong Q, Ye C-P, Jones JE, Elmquist JK, Lowell BB (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11(9):998–1000

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Tritsch NX, Ding JB, Sabatini BL (2012) Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490(7419):262–266

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Tschöp M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407(6806):908–913

    PubMed  Google Scholar 

  137. Üner A, Gonçalves GH, Li W, Porceban M, Caron N, Schönke M et al (2015) The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis. Mol Metab 4(10):678–691

    PubMed  PubMed Central  Google Scholar 

  138. Van De Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM et al (2008) Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149(4):1773–1785

    PubMed  Google Scholar 

  139. Van Den Pol A (2003) Weighing the role of hypothalamic feeding neurotransmitters. Neuron 40(6):1059–1061

    PubMed  Google Scholar 

  140. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D (2004) Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 7(5):493–494

    PubMed  Google Scholar 

  141. Volk DW, Pierri JN, Fritschy J-M, Auh S, Sampson AR, Lewis DA (2002) Reciprocal alterations in pre-and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex 12(10):1063–1070

    PubMed  Google Scholar 

  142. Vong L, Ye C, Yang Z, Choi B, Chua S, Lowell BB (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71(1):142–154

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Watson GS, Craft S (2003) The role of insulin resistance in the pathogenesis of Alzheimer’s disease. CNS Drugs 17(1):27–45

    CAS  PubMed  Google Scholar 

  144. Williams KW, Margatho LO, Lee CE, Choi M, Lee S, Scott MM et al (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30(7):2472–2479

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wilson BD, Bagnol D, Kaelin CB, Ollmann MM, Gantz I, Watson SJ, Barsh GS (1999) Physiological and anatomical circuitry between Agouti-related protein and leptin signaling 1. Endocrinology 140(5):2387–2397

    CAS  PubMed  Google Scholar 

  146. Witten IB, Steinberg EE, Lee SY, Davidson TJ, Zalocusky KA, Brodsky M et al (2011) Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72(5):721–733

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137(7):1225–1234

    PubMed  PubMed Central  Google Scholar 

  148. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R (2002) Alzheimer’s ß-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 22(10):RC221

    PubMed  Google Scholar 

  149. Xu AW, Kaelin CB, Morton GJ, Ogimoto K, Stanhope K, Graham J et al (2005) Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol 3(12):e415

    PubMed  PubMed Central  Google Scholar 

  150. Xu Y, O’Brien WG III, Lee C-C, Myers MG Jr, Tong Q (2012) Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology 153(5):2223–2233

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Xu Y, Kim ER, Zhao R, Myers MG, Munzberg H, Tong Q (2013a) Glutamate release mediates leptin action on energy expenditure. Mol Metab 2(2):109–115

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Xu Y, Wu Z, Sun H, Zhu Y, Kim ER, Lowell BB et al (2013b) Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation. Cell Metab 18(6):860–870

    CAS  PubMed  Google Scholar 

  153. Yang G, Pan F, Parkhurst CN, Grutzendler J, Gan W-B (2010) Thinned-skull cranial window technique for long-term imaging of the cortex in live mice. Nat Protoc 5(2):201–208

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Yang Y, Atasoy D, Su HH, Sternson SM (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146(6):992–1003

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U (1999) Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5(9):1066–1070

    CAS  PubMed  Google Scholar 

  156. y Cajal SR (1894) Les nouvelles idées sur la structure du système nerveux chez l’homme et chez les vertébrés: C. Reinwald, Paris

    Google Scholar 

  157. Zeltser LM, Seeley RJ, Tschöp MH (2012) Synaptic plasticity in neuronal circuits regulating energy balance. Nat Neurosci 15(10):1336–1342

    CAS  PubMed  Google Scholar 

  158. Zetsche B, Volz SE, Zhang F (2015) A split-Cas9 architecture for inducible genome editing and transcription modulation. Nat Biotechnol 33(2):139–142

    CAS  PubMed  Google Scholar 

  159. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432

    CAS  PubMed  Google Scholar 

  160. Zhang F, Gradinaru V, Adamantidis AR, Durand R, Airan RD, de Lecea L, Deisseroth K (2010) Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat Protoc 5(3):439–456

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Ziv Y, Burns LD, Cocker ED, Hamel EO, Ghosh KK, Kitch LJ et al (2013) Long-term dynamics of CA1 hippocampal place codes. Nat Neurosci 16(3):264–266

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Zuckermann M, Hovestadt V, Knobbe-Thomsen CB, Zapatka M, Northcott PA, Schramm K et al (2015) Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat Commun 6:7391

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, Tufts University School of Medicine, Tufts University, Boston, MA, USA

    Jie Xu, Christopher L. Bartolome & Dong Kong

  2. Program of Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA

    Jie Xu, Christopher L. Bartolome & Dong Kong

Authors
  1. Jie Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher L. Bartolome
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong Kong .

Editor information

Editors and Affiliations

  1. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Qi Wu

  2. Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China

    Ruimao Zheng

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Xu, J., Bartolome, C.L., Kong, D. (2018). Synaptic Regulation of Metabolism. In: Wu, Q., Zheng, R. (eds) Neural Regulation of Metabolism. Advances in Experimental Medicine and Biology, vol 1090. Springer, Singapore. https://doi.org/10.1007/978-981-13-1286-1_4

Download citation

Publish with us

Policies and ethics

Search

Navigation