Top

Published in:

01-07-2016 | Original Article

Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse

Authors: Jin Hwan Lee, Ling Wei, Todd C. Deveau, Xiaohuan Gu, Shan Ping Yu

Published in: Brain Structure and Function | Issue 6/2016

Abstract

Glutamate is an excitatory neurotransmitter in the olfactory system and its N-methyl-d-aspartate-(NMDA) receptor subunits [GluN1 (NR1), GluN2A (NR2A), and GluN2B (NR2B)] are expressed at synapses in the olfactory bulb and olfactory epithelium. Thus, glutamatergic neurons and NMDA receptors play key roles in olfaction. GluN3A (NR3A) is a unique inhibitory subunit in the NMDA receptor complex; however, the expression and functional role of GluN3A in the olfactory bulb and epithelium remain unclear. The present study examined the expression patterns of GluN3A in the olfactory bulb and epithelium and explored its functional role in the olfactory system. Immunohistochemical and Western blot analyses revealed that GluN3A is abundantly expressed in different cellular layers of the olfactory bulb and epithelium of the adult wild type (WT) mice. In littermate GluN3A knockout (GluN3A^−/−; KO) mice, the expression of olfactory marker protein normally found in mature olfactory sensory neurons was significantly reduced in the olfactory bulb and epithelium. A butyl alcohol stimulus increased immediate-early gene c-Fos expression in the olfactory system of WT mice, while this response was absent in GluN3A KO mice. The level of phosphorylated Ca²⁺/calmodulin-dependent kinase II was significantly lower in GluN3A KO mice compared to WT mice. In buried food finding test, GluN3A mice took significantly longer time to find food compared to WT mice. Consistently, impaired odor distinguishing ability was seen in GluN3A KO mice. These findings suggest that GluN3A, expressed in the adult olfactory system, plays a significant regulatory role in olfactory development and functional activity.

Al-Hallaq RA, Jarabek BR, Fu Z, Vicini S, Wolfe BB, Yasuda RP (2002) Association of NR3A with the N-methyl-d-aspartate receptor NR1 and NR2 subunits. Mol Pharmacol 62(5):1119–1127CrossRefPubMed

Baldisseri DM, Margolis JW, Weber DJ, Koo JH, Margolis FL (2002) Olfactory marker protein (OMP) exhibits a beta-clam fold in solution: implications for target peptide interaction and olfactory signal transduction. J Mol Biol 319(3):823–837. doi:10.1016/S0022-2836(02)00282-6 CrossRefPubMed

Bieri S, Monastyrskaia K, Schilling B (2004) Olfactory receptor neuron profiling using sandalwood odorants. Chem Senses 29(6):483–487. doi:10.1093/chemse/bjh050 CrossRefPubMed

Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39. doi:10.1038/361031a0 CrossRefPubMed

Buiakova OI, Baker H, Scott JW, Farbman A, Kream R, Grillo M, Franzen L, Richman M, Davis LM, Abbondanzo S, Stewart CL, Margolis FL (1996) Olfactory marker protein (OMP) gene deletion causes altered physiological activity of olfactory sensory neurons. Proc Natl Acad Sci USA 93(18):9858–9863CrossRefPubMedPubMedCentral

Chaudhury D, Manella L, Arellanos A, Escanilla O, Cleland TA, Linster C (2010) Olfactory bulb habituation to odor stimuli. Behav Neurosci 124(4):490–499. doi:10.1037/a0020293 CrossRefPubMedPubMedCentral

Chen WR, Xiong W, Shepherd GM (2000) Analysis of relations between NMDA receptors and GABA release at olfactory bulb reciprocal synapses. Neuron 25(3):625–633. pii S0896-6273(00)81065-X

Choi DW (1992) Excitotoxic cell death. J Neurobiol 23(9):1261–1276. doi:10.1002/neu.480230915 CrossRefPubMed

Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA (1995) Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 15(10):6498–6508PubMed

Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11(3):327–335CrossRefPubMed

Danciger E, Mettling C, Vidal M, Morris R, Margolis F (1989) Olfactory marker protein gene: its structure and olfactory neuron-specific expression in transgenic mice. Proc Natl Acad Sci USA 86(21):8565–8569CrossRefPubMedPubMedCentral

Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393(6683):377–381. doi:10.1038/30748 CrossRefPubMed

Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–61PubMed

Dragunow M, Faull R (1989) The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Met 29(3):261–265CrossRef

Fan J, Ngai J (2001) Onset of odorant receptor gene expression during olfactory sensory neuron regeneration. Dev Biol 229(1):119–127. doi:10.1006/dbio.2000.9972 CrossRefPubMed

Firestein S (2001) How the olfactory system makes sense of scents. Nature 413(6852):211–218. doi:10.1038/35093026 CrossRefPubMed

Guthrie KM, Anderson AJ, Leon M, Gall C (1993) Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in olfactory bulb. Proc Natl Acad Sci USA 90(8):3329–3333CrossRefPubMedPubMedCentral

Halabisky B, Friedman D, Radojicic M, Strowbridge BW (2000) Calcium influx through NMDA receptors directly evokes GABA release in olfactory bulb granule cells. J Neurosci 20(13):5124–5134. pii 20/13/5124

Henson MA, Larsen RS, Lawson SN, Perez-Otano I, Nakanishi N, Lipton SA, Philpot BD (2012) Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One 7(8):e42327. doi:10.1371/journal.pone.0042327 CrossRefPubMedPubMedCentral

Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28(3):370–490CrossRefPubMed

Hoffman GE, Smith MS, Verbalis JG (1993) c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol 14(3):173–213. doi:10.1006/frne.1993.1006 CrossRefPubMed

Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108. doi:10.1146/annurev.ne.17.030194.000335 CrossRefPubMed

Isaacson JS (2001) Mechanisms governing dendritic gamma-aminobutyric acid (GABA) release in the rat olfactory bulb. Proc Natl Acad Sci USA 98(1):337–342. doi:10.1073/pnas.021445798 PubMed

Isaacson JS, Strowbridge BW (1998) Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20(4):749–761. pii S0896-6273(00)81013-2

Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D, Frahm J, Fischer J, Bourgeron T, Ehrenreich H, Brose N (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 105(5):1710–1715. doi:10.1073/pnas.0711555105 CrossRefPubMedPubMedCentral

Kim JW, Hong SL, Lee CH, Jeon EH, Choi AR (2010) Relationship between olfactory function and olfactory neuronal population in C57BL6 mice injected intraperitoneally with 3-methylindole. Otolaryngol Head Neck Surg 143(6):837–842. doi:10.1016/j.otohns.2010.08.016 CrossRefPubMed

Larsen RS, Corlew RJ, Henson MA, Roberts AC, Mishina M, Watanabe M, Lipton SA, Nakanishi N, Perez-Otano I, Weinberg RJ, Philpot BD (2011) NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat Neurosci 14(3):338–344. doi:10.1038/nn.2750 CrossRefPubMedPubMedCentral

Laurie DJ, Seeburg PH (1994) Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J Neurosci 14(5 Pt 2):3180–3194PubMed

Lee AC, He J, Ma M (2011) Olfactory marker protein is critical for functional maturation of olfactory sensory neurons and development of mother preference. J Neurosci 31(8):2974–2982. doi:10.1523/JNEUROSCI.5067-10.2011 CrossRefPubMedPubMedCentral

Lee J, Gu X, Wei L, Wei Z, Dix TA, Yu SP (2014) Therapeutic effects of pharmacologically induced hypothermia against traumatic brain injury in mice. J Neurotrauma. doi:10.1089/neu.2013.3251

Lee JH, Wei ZZ, Chen D, Gu X, Wei L, Yu SP (2015) A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse. Am J Physiol Cell Physiol 308(7):C570–C577. doi:10.1152/ajpcell.00353.2014 CrossRefPubMedPubMedCentral

Leinders-Zufall T, Ma M, Zufall F (1999) Impaired odor adaptation in olfactory receptor neurons after inhibition of Ca²⁺/calmodulin kinase II. J Neurosci 19(14):RC19

Lethbridge R, Hou Q, Harley CW, Yuan Q (2012) Olfactory bulb glomerular NMDA receptors mediate olfactory nerve potentiation and odor preference learning in the neonate rat. PLoS One 7(4):e35024. doi:10.1371/journal.pone.0035024 CrossRefPubMedPubMedCentral

Margot C (2009) A noseful of objects. Nat Neurosci 12(7):813–814. doi:10.1038/nn0709-813 CrossRefPubMed

McBain CJ, Mayer ML (1994) N-methyl-d-aspartic acid receptor structure and function. Physiol Rev 74(3):723–760PubMed

Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130(4S Suppl):1007S–1015SPubMed

Mohamad O, Song M, Wei L, Yu SP (2013) Regulatory roles of the NMDA receptor GluN3A subunit in locomotion, pain perception and cognitive functions in adult mice. J Physiol 591(Pt 1):149–168. doi:10.1113/jphysiol.2012.239251 CrossRefPubMed

Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256(5060):1217–1221CrossRefPubMed

Neant-Fery M, Peres E, Nasrallah C, Kessner M, Gribaudo S, Greer C, Didier A, Trembleau A, Caille I (2012) A role for dendritic translation of CaMKIIalpha mRNA in olfactory plasticity. PLoS One 7(6):e40133. doi:10.1371/journal.pone.0040133 CrossRefPubMedPubMedCentral

Norlin EM, Vedin V, Bohm S, Berghard A (2005) Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse. J Neurochem 93(6):1594–1602. doi:10.1111/j.1471-4159.2005.03159.x CrossRefPubMed

Pabba M, Hristova E, Biscaro D (2012) The elusive roles of NMDA receptor amino-terminal domains. J Physiol 590(Pt 22):5561–5562. doi:10.1113/jphysiol.2012.243311 CrossRefPubMedPubMedCentral

Perez-Otano I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF (2001) Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J Neurosci 21(4):1228–1237PubMed

Roberts AC, Diez-Garcia J, Rodriguiz RM, Lopez IP, Lujan R, Martinez-Turrillas R, Pico E, Henson MA, Bernardo DR, Jarrett TM, Clendeninn DJ, Lopez-Mascaraque L, Feng G, Lo DC, Wesseling JF, Wetsel WC, Philpot BD, Perez-Otano I (2009) Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63(3):342–356. doi:10.1016/j.neuron.2009.06.016 CrossRefPubMedPubMedCentral

Schoppa NE, Kinzie JM, Sahara Y, Segerson TP, Westbrook GL (1998) Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J Neurosci 18(17):6790–6802PubMed

Shepherd GM (2004) The synaptic organization of the brain, 5th edn. Oxford University Press, Oxford, New YorkCrossRef

Smith PC, Firestein S, Hunt JF (2002) The crystal structure of the olfactory marker protein at 2.3 A resolution. J Mol Biol 319(3):807–821. doi:10.1016/S0022-2836(02)00242-5 CrossRefPubMed

Steele AD, Jackson WS, King OD, Lindquist S (2007) The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington’s and prion diseases. Proc Natl Acad Sci USA 104(6):1983–1988. doi:10.1073/pnas.0610779104 CrossRefPubMedPubMedCentral

Sucher NJ, Akbarian S, Chi CL, Leclerc CL, Awobuluyi M, Deitcher DL, Wu MK, Yuan JP, Jones EG, Lipton SA (1995) Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J Neurosci 15(10):6509–6520PubMed

Watt WC, Sakano H, Lee ZY, Reusch JE, Trinh K, Storm DR (2004) Odorant stimulation enhances survival of olfactory sensory neurons via MAPK and CREB. Neuron 41(6):955–967CrossRefPubMed

Wei J, Zhao AZ, Chan GC, Baker LP, Impey S, Beavo JA, Storm DR (1998) Phosphorylation and inhibition of olfactory adenylyl cyclase by CaM kinase II in Neurons: a mechanism for attenuation of olfactory signals. Neuron 21(3):495–504CrossRefPubMed

Wesson DW, Donahou TN, Johnson MO, Wachowiak M (2008) Sniffing behavior of mice during performance in odor-guided tasks. Chem Senses 33(7):581–596. doi:10.1093/chemse/bjn029 CrossRefPubMedPubMedCentral

Witt RM, Galligan MM, Despinoy JR, Segal R (2009) Olfactory behavioral testing in the adult mouse. J Vis Exp 23:e949. doi:10.3791/949

Wong HK, Liu XB, Matos MF, Chan SF, Perez-Otano I, Boysen M, Cui J, Nakanishi N, Trimmer JS, Jones EG, Lipton SA, Sucher NJ (2002) Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J Comp Neurol 450(4):303–317. doi:10.1002/cne.10314 CrossRefPubMed

Yang M, Crawley JN (2009) Simple behavioral assessment of mouse olfaction. Curr Protoc Neurosci Chapter 8:Unit 8 24. doi:10.1002/0471142301.ns0824s48

Youngentob SL, Mozell MM, Sheehe PR, Hornung DE (1987) A quantitative analysis of sniffing strategies in rats performing odor detection tasks. Physiol Behav 41(1):59–69CrossRefPubMed

Youngentob SL, Kent PF, Margolis FL (2003) OMP gene deletion results in an alteration in odorant-induced mucosal activity patterns. J Neurophysiol 90(6):3864–3873. doi:10.1152/jn.00806.2002 CrossRefPubMed

Zou DJ, Greer CA, Firestein S (2002) Expression pattern of alpha CaMKII in the mouse main olfactory bulb. J Comp Neurol 443(3):226–236CrossRefPubMed

Zufall F, Leinders-Zufall T (2000) The cellular and molecular basis of odor adaptation. Chem Senses 25(4):473–481CrossRefPubMed

Title: Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse
Authors: Jin Hwan Lee
Ling Wei
Todd C. Deveau
Xiaohuan Gu
Shan Ping Yu
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 6/2016
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-015-1099-3

At a glance: The STEP trials

Springer Medicine

Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2016

Distinct hippocampal functional networks revealed by tractography-based parcellation

Altered sensory processing and dendritic remodeling in hyperexcitable visual cortical networks

Characterization of connexin36 gap junctions in the human outer retina

Anxiety is related to indices of cortical maturation in typically developing children and adolescents

Structural brain aging and speech production: a surface-based brain morphometry study

Cerebral functional connectivity periodically (de)synchronizes with anatomical constraints