Nitric oxide (NO) is widely used in neural circuits giving rise to learning and memory. NO is an unusual neurotransmitter in its modes of release and action. Is its association with learning and memory related to its unusual properties? Reviewing the literature might allow the formulation of a general principle on how NO and memory are related. However, other than confirming that there is indeed a strong association between NO and memory, no simple rules emerge on the role of NO in learning and memory. The effects of NO are not associated with a particular stage or form of memory and are highly dependent on species, strain, and behavior or training paradigm. Nonetheless, a review does provide hints on why NO is associated with learning and memory. Unlike transmitters acting via receptors expressed only in neurons designed to respond to the transmitter, NO is a promiscuous signal that can affect a wide variety of neurons, via many molecular mechanisms. In circuits giving rise to learning and memory, it may be useful to signal some events via a promiscuous messenger having widespread effects. However, each circuit will use the promiscuous signal in a different way, to achieve different ends.
Get full access to this article
View all access options for this article.
References
1.
Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. 1997. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell88: 615-626.
2.
Ahern GP, Klyachko VA, Jackson MB. 2002. cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO. Trends Neurosci25: 510-517.
3.
Allen MT, Steinmetz JE. 1996. A nitric oxide synthase inhibitor delays the formation of learning-related neural activity in the cerebellar interpositus nucleus during rabbit eyelid conditioning. Pharmacol Biochem Behav53: 147-153.
4.
Arancio O, Antonova I, Gambaryan S, Lohmann SM, Wood JS, Lawrence DS, and others. 2001. Presynaptic role of cGMP-dependent protein kinase during long-lasting potentiation. J Neurosci21: 143-149.
5.
Arancio O, Kiebler M, Lee CJ, Lev-Ram V, Tsien RY, Kandel ER, and others. 1996. Nitric oxide acts directly in the presynaptic neuron to produce long-term potentiation in cultured hippocampal neurons Cell87: 1025-1035.
6.
Bannerman DM, Chapman PF, Kelly PA, Butcher SP, Morris RG. 1994a. Inhibition of nitric oxide synthase does not impair spatial learning. J Neurosci14: 7404-7414.
7.
Bannerman DM, Chapman PF, Kelly PA, Butcher SP, Morris RG. 1994b. Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo. J Neurosci14: 7415-7425.
8.
Baratti CR, Kopf SR. 1996. A nitric oxide synthase inhibitor impairs memory storage in mice. Neurobiol Learn Mem65: 197-201.
9.
Bear MF, Abraham WC. 1996. Long-term depression in hippocampus. Annu Rev Neurosci19: 437-462.
10.
Blackshaw S, Eliasson MJ, Sawa A, Watkins CC, Krug D, Gupta A, and others. 2003. Species, strain and developmental variations in hippocampal neuronal and endothelial nitric oxide synthase clarify discrepancies in nitric oxide-dependent synaptic plasticity. Neurosci119: 979-990.
11.
Böhme GA, Bon C, Lemaire M, Reibaud M, Piot O, Stutzmann JM, and others. 1993. Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats. Proc Natl Acad Sci U S A90: 9191-9194.
12.
Bolshakov VY, Siegelbaum SA. 1995. Regulation of hippocampal transmitter release during development and long-term potentiation. Science269: 1730-1734.
13.
Bon CL, Garthwaite J. 2003. On the role of nitric oxide in hippocampal long-term potentiation. J Neurosci23: 1941-1948.
14.
Botzer D, Markovich S, Susswein AJ. 1998. Multiple memory processes following training that a food is inedible in Aplysia. Learn Mem5: 204-219.
15.
Boyden ES, Raymond JL. 2003. Active reversal of motor memories reveals rules governing memory encoding. Neuron39: 1031-1042.
16.
Bredt DS, Snyder SH. 1989. Nitric oxide mediates glutamate linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A86: 9030-9033.
Byrne JH, Kandel ER. 1996. Presynaptic facilitation revisited: state and time dependence J Neurosci16: 425-435.
20.
Cummings JA, Nicola SM, Malenka RC. 1994. Induction in the rat hippocampus of long-term potentiation (LTP) and long-term depression (LTD) in the presence of a nitric oxide synthase inhibitor. Neurosci Lett176: 110-114.
21.
Dev KK, Morris BJ. 1994. Modulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding sites by nitric oxide. J Neurochem63: 946-952.
22.
Emptage NJ, Reid CA, Fine A, Bliss TV. 2003. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron38: 797-804.
23.
Feldman PL, Grif OW, Stuehr DJ. 1993. The surprising life of nitric oxide. Chem Eng News26-38.
24.
Fin C, da Cunha C, Bromberg E, Schmitz PK, Bianchin M, Medina JH, and others. 1995. Experiments suggesting a role for nitric oxide in the hippocampus in memory processes. Neurobiol Learn Mem63: 113-115.
25.
Frey U, Frey S, Schollmeier F, Krug M. 1996. Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro. J Physiol490: 703-711.
26.
Frey U, Krug M, Reymann KG, Matthies H. 1988. Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res452: 57-65.
27.
Ghirardi M, Montarolo PG, Kandel ER. 1995. A novel intermediate stage in the transition between short- and long-term facilitation in the sensory to motor neuron synapse of Aplysia. Neuron14: 413-420.
28.
Greengard P. 2001. The neurobiology of slow synaptic transmission. Science294: 1024-1030.
29.
Hartell NA. 1994. Induction of cerebellar long-term depression requires activation of glutamate metabotropic receptors. Neuroreport5: 913-916.
30.
Hölscher C. 2002. Different strains of rats show different sensitivity to block of long-term potentiation by nitric oxide synthase inhibitors. Eur J Pharmacol457: 99-106.
31.
Hölscher C, Rose S. 1993. Inhibiting synthesis of the putative retro-grade messenger nitric oxide results in amnesia in a passive avoidance task in the chick. Brain Res619: 189-194.
32.
Ito M. 2001. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev81: 1143-1195.
33.
Jacklet JW, Koh H-Y. 2001. Nitric oxide as an orthograde cotransmitter at central synapses of Aplysia: responses of isolated neurons in culture. Am Zool41: 282-291.
34.
Jacoby S, Sims RE, Hartell NA. 2001. Nitric oxide is required for the induction and heterosynaptic spread of long-term potentiation in rat cerebellar slices. J Physiol535: 825-839.
35.
Kandel ER. 2001. The molecular biology of memory storage: a dialogue between genes and synapses. Science294: 1030-1038.
36.
Katzoff A, Ben-Gedalya T, Susswein AJ. 2002. Nitric oxide is necessary for multiple memory processes after learning that a food is inedible in Aplysia. J Neurosci22: 9581-9594.
37.
Kemenes I, Kemenes G, Andrew RJ, Benjamin PR, O’Shea M. 2002. Critical time-window for NO-cGMP-dependent long-term memory formation after one-trial appetitive conditioning. J Neurosci22: 1414-1425.
38.
Kendrick KM, Guevara-Guzman R, Zorrilla J, Hinton MR, Broad KD, Mimmack M, and others. 1997. Formation of olfactory memories mediated by nitric oxide. Nature388: 670-674.
39.
Kleppisch T, Pfeifer A, Klatt P, Ruth P, Montkowski A, Fassler R, and others. 1999. Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinases is normal and susceptible to inhibition of nitric oxide synthase. J Neurosci19: 48-55.
40.
Kleppisch T, Wolfsgruber W, Feil S, Allmann R, Wotjak CT, Goebbels S, and others. 2003. Hippocampal cGMP-dependent protein kinase I supports an age- and protein synthesis-dependent component of long-term potentiation but is not essential for spatial reference and contextual memory. J Neurosci23: 6005-6012.
41.
Ko GY, Kelly PT. 1999. Nitric oxide acts as a postsynaptic signaling molecule in calcium/calmodulin-induced synaptic potentiation in hippocampal CA1 pyramidal neurons. J Neurosci19: 6784-6794.
42.
Lev-Ram V, Jiang T, Wood J, Lawrence DS, Tsien RY. 1997. Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron18: 1025-1038.
43.
Lev-Ram V, Wong ST, Storm DR, Tsien RY. 2002. A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP. Proc Natl Acad Sci U S A99: 8389-8393.
44.
Li J, Smith SS, McElligott JG. 1995. Cerebellar nitric oxide is necessary for vestibulo-ocular reflex adaptation, a sensorimotor model of learning. J Neurophysiol74: 489-494.
45.
Linden DJ. 1996. A protein synthesis-dependent late phase of cerebellar long-term depression. Neuron17: 483-490.
46.
Lu YF, Kandel ER, Hawkins RD. 1999. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci19: 10250-10261.
47.
Lüscher C, Nicoll RA, Malenka RC, Muller D. 2000. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nature Neurosci3: 545-550.
Mauk MD, Garcia KS, Medina JF, Steele PM. 1998. Does cerebellar LTD mediate motor learning? Toward a resolution without a smoking gun. Neuron20: 359-362.
Milner B, Squire LR, Kandel ER. 1998. Cognitive neuroscience and the study of memory. Neuron20: 445-468.
52.
Mogensen J, Wortwein G, Hasman A, Nielsen P, Wang Q. 1995. Functional and neurochemical profile of place learning after L-nitroarginine in the rat. Neurobiol Learn Mem63: 54-65.
53.
Monfort P, Muñoz MD, Kosenko E, Felipo V. 2002. Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. J Neurosci22: 10116-10122.
54.
Müller U. 1996. Inhibition of nitric oxide synthase impairs a distinct form of long-term memory in the honeybee, Apis mellifera. Neuron16: 541-549.
55.
Müller U. 2000. Prolonged activation of cAMP-dependent protein kinase during conditioning induces long-term memory in honey-bees. Neuron27: 159-168.
56.
Müller U, Hildebrandt H. 2002. Nitric oxide/cGMP-mediated protein kinase A activation in the antennal lobes plays an important role in appetitive reflex habituation in the honeybee. J Neurosci22: 8739-8747.
57.
Murphy KP, Bliss TV. 1999. Photolytically released nitric oxide produces a delayed but persistent suppression of LTP in area CA1 of the rat hippocampal slice. J Physiol515: 453-462.
58.
Murphy KP, Williams JH, Bettache N, Bliss TV. 1994. Photolytic release of nitric oxide modulates NMDA receptor-mediated transmission but does not induce long-term potentiation at hippocampal synapses. Neuropharmacol33: 1375-1385.
59.
Nagao S, Kitazawa H, Osanai R, Hiramatsu T. 1997. Acute effects of tetrahydrobiopterin on the dynamic characteristics and adaptability of vestibulo-ocular reflex in normal and flocculus lesioned rabbits. Neurosci Lett231: 41-44.
60.
Nakazawa K, Mikawa S, Hashikawa T, Ito M. 1995. Transient and persistent phosphorylation of AMPA-type glutamate receptor subunits in cerebellar Purkinje cells. Neuron15: 697-709.
61.
Okere CO, Kaba H. 2000. Increased expression of neuronal nitric oxide synthase mRNA in the accessory olfactory bulb during the formation of olfactory recognition memory in mice. Eur J Neurosci12: 4552-4556.
62.
Okere CO, Kaba H, Higuchi T. 1996. Formation of an olfactory recognition memory in mice: reassessment of the role of nitric oxide. Neurosci71: 349-354.
63.
Park JH, Straub VA, O’Shea M. 1998. Anterograde signaling by nitric oxide: characterization and in vitro reconstitution of an identified nitrergic synapse. J Neurosci18: 5463-5476.
64.
Prast H, Philippu A. 2001. Nitric oxide as modulator of neuronal function. Prog Neurobiol64: 51-68.
65.
Rand MJ, Li CG. 1995. Nitric oxide as a neurotransmitter in peripheral nerves: nature of transmitter and mechanism of transmission. Ann Rev Physiol57: 659-682.
66.
Raymond JL, Lisberger SG. 1996. Behavioral analysis of signals that guide learned changes in the amplitude and dynamics of the vestibulo-ocular reflex. J Neurosci16: 7791-7802.
67.
Rickard NS, Ng KT, Gibbs ME. 1998. Further support for nitric oxide-dependent memory processing in the day-old chick. Neurobiol Learn Mem69: 79-86.
68.
Robertson JD, Bonaventura J, Kohm A. 1995. Nitric oxide synthase inhibition blocks Octopus touch learning without producing sensory or motor dysfunction. Proc R Soc Lond B Biol Sci261: 167-172.
69.
Robertson JD, Bonaventura J, Kohm A, Hiscat M. 1996. Nitric oxide is necessary for visual learning in Octopus vulgaris. Proc R Soc Lond B Biol Sci263: 1739-1743.
70.
Samama B, Boehm N. 1999. Inhibition of nitric oxide synthase impairs early olfactory associative learning in newborn rats. Neurobiol Learn Mem71: 219-231.
71.
Schuman EM, Madison DV. 1991. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science254: 1503-1506.
72.
Schuman EM, Madison DV. 1994. Locally distributed synaptic potentiation in the hippocampus. Science263: 532-536.
73.
Schuman EM, Meffert MK, Schulman H, Madison DV. 1994. An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation. Proc Natl Acad Sci U S A91: 11958-11962.
74.
Selig DK, Segal MR, Liao D, Malenka RC, Malinow R, Nicoll RA, and others. 1996. Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus. Learn Mem3: 42-48.
75.
Shors TJ, Matzel LD. 1997. Long-term potentiation: what’s learning got to do with it? Behav Brain Sci20: 597-614.
76.
Smith SL, Otis TS. 2003. Persistent changes in spontaneous firing of Purkinje neurons triggered by the nitric oxide signaling cascade. J Neurosci23: 367-372.
77.
Son H, Hawkins RD, Martin K, Kiebler M, Huang PL, Fishman MC, and others. 1996. Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell87: 1015-1023.
78.
Son H, Lu YF, Zhuo M, Arancio O, Kandel ER, Hawkins RD. 1998. The specific role of cGMP in hippocampal LTP. Learn Mem5: 231-245.
79.
Sutton MA, Masters SE, Bagnall MW, Carew TJ. 2001. Molecular mechanisms underlying a unique intermediate phase of memory in Aplysia. Neuron19: 143-154.
80.
Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, and others. 1999. Genetic enhancement of learning and memory in mice. Nature401: 63-69.
81.
Teyke T. 1996. Nitric oxide, but not serotonin, is involved in acquisition of food-attraction conditioning in the snail Helix pomatia. Neurosci Lett206: 29-32.
82.
Tobin JR, Gorman LK, Baxter MG, Traystman RJ. 1995. Nitric oxide synthase inhibition does not impair visual or spatial discrimination learning. Brain Res694: 177-182.
83.
Tsien JZ, Huerta PT, Tonegawa S. 1996. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell87: 1327-1338.
84.
Umans JG, Levi R. 1995. Nitric oxide in the regulation of blood flow and arterial pressure. Ann Rev Physiol57: 771-790.
85.
Wang JH, Kelly P. 1995. Postsynaptic injection of Ca2+/CaM induces synaptic potentiation requiring CaM-KII and PKC activity. Neuron15: 443-452.
86.
Wu J, Wang Y, Rowan MJ, Anwyl R. 1998. Evidence for involvement of the cGMP-protein kinase G signaling system in the induction of long-term depression, but not long-term potentiation, in the dentate gyrus in vitro. J Neurosci18: 3589-3596.
87.
Zhuo M, Hu Y, Schultz C, Kandel ER, Hawkins RD. 1994a. Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature368: 635-639.
88.
Zhuo M, Kandel ER, Hawkins RD. 1994b. Nitric oxide and cGMP can produce either synaptic depression or potentiation depending on the frequency of presynaptic stimulation in the hippocampus. Neuroreport5: 1033-1036.
89.
Zhuo M, Small SA, Kandel ER, Hawkins RD. 1993. Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science260: 1946-1950.
