Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons
Open accessAbstract
Hypocretin/orexin neurons play an important role in hypothalamic arousal. Synaptic glutamate input to hypocretin neurons regulates cell firing. We studied the actions of group III metabotropic glutamate receptors (mGluRs) in modulating the activity of hypocretin neurons using whole-cell voltage- and current-clamp recording in mouse whole hypothalamic slices or minislices consisting only of the lateral hypothalamus. Selective green fluorescent protein expression was used to detect live hypocretin neurons. The mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP-4) inhibited synaptic input to hypocretin neurons in a dose-dependent manner; both spontaneous glutamate and GABA-mediated synaptic currents were reduced in frequency. l-AP-4 also reduced the amplitude of postsynaptic potentials evoked by a stimulating electrode placed medial or lateral to the recorded cell. No postsynaptic effect of l-AP-4 was found relative to membrane potential, input resistance, or AMPA-evoked currents. l-AP-4 appeared to act by a presynaptic mechanism and reduced the frequency of both glutamate- and GABA-mediated miniature events recorded in the presence of tetrodotoxin, with no change in amplitude. (RS)-phosphonopentanoic acid (CPPG), a group III mGluR antagonist, suppressed the actions of l-AP-4. Of substantial interest, CPPG by itself increased synaptic activity recorded in hypocretin neurons, suggesting an ongoing inhibitory tone attributable to activation of group III mGluRs. Glutamatergic interneurons have been suggested to play a role in a positive feedback recruitment of hypocretin on hypocretin neurons. l-AP-4 blocked hypocretin-mediated increases in EPSCs and attenuated the hypocretin-mediated increase in spike frequency. Together, these data suggest that tonically active inhibitory mGluRs are expressed on local hypocretin-sensitive glutamate neurons within the lateral hypothalamus that modulate the output of the hypocretin arousal system.
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Group III metabotropic receptors inhibit excitatory inputs to the lateral hypothalamus.
“Group III metabotropic receptors have also been shown to inhibit excitatory inputs to the lateral hypothalamus (Acuna-Goycolea et al., 2004), while Group I metabotropic receptors stimulate both oxytocin and vasopressin release from the SON (Morsette et al., 2001).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Acuna-Goycolea et al., 2004
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Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
Narcolepsy in orexin Knockout Mice
Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)81973-x · Cited by 3,095 · see citing works
Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, P. J., Nishino, S., & Mignot, E. (1999) · Cell · doi:10.1016/s0092-8674(00)81965-0 · Cited by 2,613 · see citing works
Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., et al. (2000) · Nature Medicine · doi:10.1038/79690 · Cited by 2,118 · see citing works
Reduced Number of Hypocretin Neurons in Human Narcolepsy
Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., & Siegel, J. M. (2000) · Neuron · doi:10.1016/s0896-6273(00)00058-1 · Cited by 2,089 · see citing works
Hypocretin (orexin) deficiency in human narcolepsy
Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., & Mignot, E. (2000) · The Lancet · doi:10.1016/s0140-6736(99)05582-8 · Cited by 1,776 · see citing works
Orexin A activates locus coeruleus cell firing and increases arousal in the rat
Hagan, J. J., Leslie, R. A., Patel, S., Evans, M. L., Wattam, T. A., Holmes, S., Benham, C. D., Taylor, S. G., Routledge, C., Hemmati, P., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.19.10911 · Cited by 1,234 · see citing works
Shigemoto, R., Kinoshita, A., Wada, E., Nomura, S., Ohishi, H., Takada, M., Flor, P. J., Neki, A., Abe, T., Nakanishi, S., et al. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-19-07503.1997 · Cited by 1,116 · see citing works
Hypothalamic Orexin Neurons Regulate Arousal According to Energy Balance in Mice
Yamanaka, A., Beuckmann, C. T., Willie, J. T., Hara, J., Tsujino, N., Mieda, M., Tominaga, M., Yagami, K.-I., Sugiyama, F., Goto, K., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00331-3 · Cited by 936 · see citing works
Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors
Cartmell, J., & Schoepp, D. D. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750889.x · Cited by 883 · see citing works
Metabotropic glutamate receptors: Synaptic transmission, modulation, and plasticity
Nakanishi, S. (1994) · Neuron · doi:10.1016/0896-6273(94)90043-4 · Cited by 716 · see citing works
Schoepp, D. D. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29296-x · Cited by 693 · see citing works
GABA: A dominant neurotransmitter in the hypothalamus
Decavel, C., & van den Pol, A. N. (1990) · The Journal of Comparative Neurology · doi:10.1002/cne.903020423 · Cited by 571 · see citing works
van den Pol, A. N., Gao, X., Obrietan, K. H., Kilduff, T. S., & Belousov, A. B. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-19-07962.1998 · Cited by 552 · see citing works
Synaptic Activation of Glutamate Transporters in Hippocampal Astrocytes
Bergles, D. E., & Jahr, C. E. (1997) · Neuron · doi:10.1016/s0896-6273(00)80420-1 · Cited by 516 · see citing works
Orexin/Hypocretin Excites the Histaminergic Neurons of the Tuberomammillary Nucleus
Eriksson, K. S., Sergeeva, O. A., Brown, R. E., & Haas, H. L. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-23-09273.2001 · Cited by 509 · see citing works
Li, Y., Gao, X., Sakurai, T., & van den Pol, A. N. (2002) · Neuron · doi:10.1016/s0896-6273(02)01132-7 · Cited by 476 · see citing works
Self-citationScanziani, M., Salin, P. A., Vogt, K. E., Malenka, R. C., & Nicoll, R. A. (1997) · Nature · doi:10.1038/385630a0 · Cited by 456 · see citing works
Liu, R.-J., van den Pol, A. N., & Aghajanian, G. K. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09453.2002 · Cited by 392 · see citing works
Burlet, S., Tyler, C. J., & Leonard, C. S. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-07-02862.2002 · Cited by 284 · see citing works
Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2
Rosin, D. L., Weston, M. C., Sevigny, C. P., Stornetta, R. L., & Guyenet, P. G. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10860 · Cited by 252 · see citing works
Quantal events shape cerebellar interneuron firing
Carter, A. G., & Regehr, W. G. (2002) · Nature Neuroscience · doi:10.1038/nn970 · Cited by 214 · see citing works
Bradley, S., Levey, A. I., Hersch, S. M., & Conn, P. J. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-06-02044.1996 · Cited by 209 · see citing works
Glutamate receptors in the rat hypothalamus and pituitary.
Meeker, R. B., Greenwood, R., & Hayward, J. N. (1994) · Endocrinology · doi:10.1210/endo.134.2.7905409 · Cited by 187 · see citing works
Modulation of GABAergic Signaling among Interneurons by Metabotropic Glutamate Receptors
Semyanov, A. V., & Kullmann, D. M. (2000) · Neuron · doi:10.1016/s0896-6273(00)81068-5 · Cited by 184 · see citing works
Glutamate neurons in hypothalamus regulate excitatory transmission
van den Pol, A., & Trombley, P. (1993) · Journal of Neuroscience · doi:10.1523/jneurosci.13-07-02829.1993 · Cited by 167 · see citing works
Group III Metabotropic Glutamate Receptor-Mediated Modulation of the Striatopallidal Synapse
Valenti, O., Marino, M. J., Wittmann, M., Lis, E. V., DiLella, A. G., Kinney, G. G., & Conn, P. J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07218.2003 · Cited by 166 · see citing works
The posterior hypothalamic area: chemoarchitecture and afferent connections
Abrahamson, E. E., & Moore, R. Y. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03015-8 · Cited by 149 · see citing works
Daftary, S. S., Boudaba, C., Szabó, K., & Tasker, J. G. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-24-10619.1998 · Cited by 145 · see citing works
Schrader, L. A., & Tasker, J. G. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.77.2.527 · Cited by 144 · see citing works
Feng, D., Nagy, J. A., Hipp, J. A., Pyne, K., Dvorak, H. F., & Dvořàk, A. M. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.747bd.x · Cited by 115 · see citing works
Peever, J. H., Lai, Y., & Siegel, J. M. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00968.2002 · Cited by 95 · see citing works
Distribution and Developmental Regulation of Metabotropic Glutamate Receptor 7a in Rat Brain
Bradley, S. R., Rees, H. D., Yi, H., Levey, A. I., & Conn, P. J. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71020636.x · Cited by 94 · see citing works
Kombian, S., Hirasawa, M., Mouginot, D., Chen, X., & Pittman, Q. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.83.5.2542 · Cited by 82 · see citing works
Glutamate Inhibits GABA Excitatory Activity in Developing Neurons
van den Pol, A. N., Gao, X., Patrylo, P. R., Ghosh, P. K., & Obrietan, K. H. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-24-10749.1998 · Cited by 81 · see citing works
Awatramani, G. B., & Slaughter, M. M. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00741.2001 · Cited by 81 · see citing works
Toms, N. J., Jane, D. E., Kemp, M. C., Bedingfield, J. S., & Roberts, P. (1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb15750.x · Cited by 77 · see citing works
Dougherty, K. D., & Milner, T. A. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19990428)407:1 · Cited by 76 · see citing works
Losonczy, A., Somogyi, P., & Nusser, Z. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00842.2002 · Cited by 72 · see citing works
Glutamate receptors in the rat hypothalamus and pituitary
Meeker, R. B. (1994) · Endocrinology · doi:10.1210/en.134.2.621 · Cited by 71 · see citing works
Smith, B. N., & Dudek, F. E. (2002) · Journal of Neurophysiology · doi:10.1152/jn.00581.2001 · Cited by 69 · see citing works
Martin, G. E., Nie, Z., & Siggins, G. R. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.78.6.3028 · Cited by 64 · see citing works
Arshavsky, V. Y. (2002) · Neuron · doi:10.1016/s0896-6273(02)00937-6 · Cited by 58 · see citing works
Ghosh, P. K., Baskaran, N., & van den Pol, A. N. (1997) · Developmental Brain Research · doi:10.1016/s0165-3806(97)00066-7 · Cited by 56 · see citing works
Gordon, G. R., & Bains, J. S. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06223.2003 · Cited by 51 · see citing works
Local synaptic release of glutamate from neurons in the rat hypothalamic arcuate nucleus.
Belousov, A. B., & van den Pol, A. N. (1997) · The Journal of Physiology · doi:10.1113/jphysiol.1997.sp021966 · Cited by 47 · see citing works
Evans, D. I., Jones, R. S. G., & Woodhall, G. L. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.83.5.2519 · Cited by 43 · see citing works
Activity-Dependent Activation of Presynaptic Metabotropic Glutamate Receptors in Locus Coeruleus
Dubé, G., & Marshall, K. C. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.83.3.1141 · Cited by 40 · see citing works
Awad, H., & Conn, P. J. (2001) · Neuropharmacology · doi:10.1016/s0028-3908(01)00047-8 · Cited by 37 · see citing works
Macek, T. A., Schaffhauser, H., & Conn, P. J. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb11327.x · Cited by 22 · see citing works
Chen, G., & van den Pol, A. N. (1998) · Journal of Neurophysiology · doi:10.1152/jn.1998.80.4.1932 · Cited by 21 · see citing works
Taverna, S., & Pennartz, C. M. A. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02676-3 · Cited by 10 · see citing works
Horvath (1999) · doi:10.1002/(sici)1096-9861(19991213)415:2
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Extracellular glutamate: functional compartments operate in different concentration ranges
Moussawi, K., Riegel, A., Nair, S., & Kalivas, P. W. (2011) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2011.00094 · Cited by 184 · see citing works
de Lecea, L., & Sutcliffe, J. G. (2005) · The FEBS Journal · doi:10.1111/j.1742-4658.2005.04981.x · Cited by 105 · see citing works
Duvoisin, R. M., Zhang, C., Pfankuch, T. F., O'Connor, H., Gayet‐Primo, J., Quraishi, S., & Raber, J. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04210.x · Cited by 102 · see citing works
Glutamate receptors in domestication and modern human evolution
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- Authors
- Acuna-Goycolea, C., Li, Y., & van den Pol, A. N.
- Affiliations
- Yale University (US)
- ORCID
- Li, Ying
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-03-24
- Volume
- 24
- Issue
- 12
- Pages
- 3013-3022
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729849
- OpenAlex
- W2056060248
- Cited by
- 69
- References
- 53
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS 41454, R01NS041454, NS 34887, R01NS034887)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- group III metabotropic glutamate receptors, hypocretin/orexin neurons, tonic inhibition, lateral hypothalamus, L-AP4, presynaptic inhibition, glutamatergic interneurons, GABAergic inhibition, excitatory synaptic input, arousal system, positive feedback
- MeSH terms
- Orexins, Action Potentials, Animals, Arousal, Carrier Proteins, Dose-Response Relationship, Drug, Electric Stimulation, Hypothalamus, Luminescent Proteins, Mice, Transgenic, Neural Inhibition, Synaptic Transmission, Neurons, Neuropeptides, Receptors, Neuropeptide, Receptors, Metabotropic Glutamate, Patch-Clamp Techniques, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Feedback, Physiological, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Mice, Orexin Receptors, In Vitro Techniques
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