Restricted accessResearch articleFirst published online 2020-03
N -Methyl- d -Aspartate Receptor Modulation by Nicotinamide Adenine Dinucleotide Phosphate Oxidase Type 2 Drives Synaptic Plasticity and Spatial Memory Impairments in Rats Exposed Pre- and Postnatally to Ethanol
Pre- and/or early postnatal ethanol exposure (prenatal alcohol exposure [PAE]) impairs synaptic plasticity as well as memory formation, but the mechanisms underlying these effects remain unclear. Both long-term potentiation (LTP) and spatial memory formation in the hippocampus involve the nicotinamide adenine dinucleotide phosphate oxidase type 2 (NOX2) enzyme. Previous studies have reported that N-methyl-d-aspartate receptor (NMDAR) activation increases NOX2-mediated superoxide generation, resulting in inhibition of NMDAR function, but whether NOX2 impacts NMDAR function in PAE animals leading to impaired LTP and memory formation remains unknown. We aim to evaluate whether the NOX2-NMDAR complex is involved in the long-lasting deleterious effects of PAE on hippocampal LTP and memory formation.
Results:
Here we provide novel evidence that PAE animals display impaired NMDAR-dependent LTP in the cornus ammonis field 1 (CA1) and NMDAR-mediated LTP in the dentate gyrus (DG). Moreover, PAE rats displayed increased NMDAR-mediated transmission in both hippocampal areas. Interestingly, NOX2 pharmacological inhibition restored NMDAR-mediated transmission and LTP in the CA1, but not in the DG. PAE also induced overexpression of NOX2 and CaMKII isoforms, but did not modify the content or the redox state of the N-methyl-d-aspartate receptor subunit-1 (NR1) subunit of NMDAR in both areas of the hippocampus. In addition, adolescent PAE rats orally fed the antioxidant and free radical scavenger apocynin exhibited significantly improved spatial memory acquisition.
Innovation and Conclusion:
By showing in PAE animals NOX2 overexpression and increased NMDAR-mediated transmission, which might lead to impaired synaptic plasticity and memory formation in a region-specific manner, we provide an important advance to our current understanding of the cellular mechanisms underlying PAE-dependent defective hippocampal function.
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References
1.
AizenmanE, LiptonSA, and LoringRH. Selective modulation of NMDA responses by reduction and oxidation. Neuron, 2: 1257–1263, 1989.
2.
AltenhöferS, RadermacherKA, KleikersPWM, WinglerK, and SchmidtHHHW. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal, 23: 406–427, 2015.
3.
AugsburgerF, FilippovaA, RastiD, SeredeninaT, LamM, MaghzalG, MahioutZ, Jansen-DürrP, KnausUG, DoroshowJ, StockerR, KrauseK-H, and JaquetV. Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biol, 26: 101272, 2019.
4.
BeckhauserTF, Francis-OliveiraJ, and De PasqualeR. Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci, 10: 23–48, 2016.
5.
BradyML, AllanAM, and CaldwellKK. A limited access mouse model of prenatal alcohol exposure that produces long-lasting deficits in hippocampal-dependent learning and memory. Alcohol Clin Exp Res, 36: 457–466, 2012.
6.
BradyML, DiazMR, IusoA, EverettJC, ValenzuelaCF, and CaldwellKK. Moderate prenatal alcohol exposure reduces plasticity and alters NMDA receptor subunit composition in the dentate gyrus. J Neurosci, 33: 1062–1067, 2013.
7.
BrennanAM, SuhSW, WonSJ, NarasimhanP, KauppinenTM, LeeH, EdlingY, ChanPH, and SwansonRA. NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci, 12: 857–863, 2009.
8.
BrocardoPS, Gil-MohapelJ, and ChristieBR. The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res Rev, 67: 209–225, 2011.
9.
CarvalhoAL, DuarteCB, and CarvalhoAP. Regulation of AMPA receptors by phosphorylation. Neurochem Res, 25: 1245–1255, 2000.
10.
ChavezAE, ChiuCQ, and CastilloPE. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci, 13: 1511–1518, 2010.
11.
ChavezAE, HernandezVM, Rodenas-RuanoA, ChanCS, and CastilloPE. Compartment-specific modulation of GABAergic synaptic transmission by TRPV1 channels in the dentate gyrus. J Neurosci, 34: 16621–16629, 2014.
12.
ChenH-B, LiF, WuS, and AnS-C.[Hippocampus quinolinic acid modulates glutamate and NMDAR/mGluR1 in chronic unpredictable mild stress-induced depression]. Sheng Li Xue Bao, 65: 577–585, 2013 (Article in Chinese).
13.
ChoiY, ChenHV, and LiptonSA. Three pairs of cysteine residues mediate both redox and zn2+ modulation of the nmda receptor. J Neurosci, 21: 392–400, 2001.
14.
ChristieBR, SwannSE, FoxCJ, FrocD, LieblichSE, RedilaV, and WebberA. Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male rats. Eur J Neurosci, 21: 1719–1726, 2005.
15.
ColesCD, GoldsteinFC, LynchME, ChenX, KableJA, JohnsonKC, and HuX. Memory and brain volume in adults prenatally exposed to alcohol. Brain Cogn, 75: 67–77, 2011.
16.
ContrerasML, de la Fuente-OrtegaE, Vargas-RobertsS, MuñozDC, GoicCA, and HaegerPA. NADPH oxidase isoform 2 (NOX2) is involved in drug addiction vulnerability in progeny developmentally exposed to ethanol. Front Neurosci, 11: 338, 2017.
17.
CsányiG, Cifuentes-PaganoE, Al GhouleñI, RanayhossainiDJ, EgañaL, LopesLR, JacksonHM, KelleyEE, and PaganoPJ. Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med, 51: 1116–1125, 2011.
18.
De La Fuente-OrtegaE, Plaza-BriceñoW, Vargas-RobertS, and HaegerP. Prenatal ethanol exposure misregulates genes involved in iron homeostasis promoting a maladaptation of iron dependent hippocampal synaptic transmission and plasticity. Front Pharmacol, 10: 1312, 2019.
19.
Diaz-GranadosJL, Spuhler-PhillipsK, LilliquistMW, AmselA, and LeslieSW. Effects of prenatal and early postnatal ethanol exposure on [3H]MK-801 binding in rat cortex and hippocampus. Alcohol Clin Exp Res, 21: 874–881, 1997.
20.
DuganLL, AliSS, ShekhtmanG, RobertsAJ, LuceroJ, QuickKL, and BehrensMM. IL-6 Mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. PLoS One, 4: e5518, 2009.
21.
FontaineCJ, PinarC, YangW, PangAF, SuesserKE, ChoiJSJ, and ChristieBR. Impaired bidirectional synaptic plasticity in juvenile offspring following prenatal ethanol exposure. Alcohol Clin Exp Res, 43: 2153–2166, 2019.
22.
GalindoR, FraustoS, WolffC, CaldwellKK, Perrone-BizzozeroNI, and SavageDD. Prenatal ethanol exposure reduces mGluR5 receptor number and function in the dentate gyrus of adult offspring. Alcohol Clin Exp Res, 28: 1587–1597, 2004.
23.
GirouardH, WangG, GalloEF, AnratherJ, ZhouP, PickelVM, and IadecolaC. NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci, 29: 2545–2552, 2009.
24.
HarrazMM, MardenJJ, ZhouW, ZhangY, WilliamsA, SharovVS, NelsonK, LuoM, PaulsonH, SchöneichC, and EngelhardtJF. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest, 118: 659–670, 2008.
25.
HillAJ, DreverN, YinH, TamayoE, SaadeG, and BytautieneE. The role of NADPH oxidase in a mouse model of fetal alcohol syndrome. Am J Obstet Gynecol, 210: 466.e1–466.e5, 2014.
26.
HillBG, ReilyC, OhJY, JohnsonMS, and LandarA. Methods for the determination and quantification of the reactive thiol proteome. Free Radic Biol Med, 47: 675–683, 2009.
HonseY, NixonK, BrowningM, and LeslieS. Cell surface expression of NR1 splice variants and NR2 subunits is modified by prenatal ethanol exposure. Neuroscience, 122: 689–698, 2003.
29.
IbiM, LiuJ, ArakawaN, KitaokaS, KawajiA, MatsudaKI, IwataK, MatsumotoM, KatsuyamaM, ZhuK, TeramukaiS, FuruyashikiT, and Yabe-NishimuraC. Depressive-like behaviors are regulated by NOX1/NADPH oxidase by redox modification of NMDA receptor 1. J Neurosci, 37: 4200–4212, 2017.
30.
IzumiY, KitabayashiR, FunatsuM, IzumiM, YuedeC, HartmanRE, WozniakDF, and ZorumskiCF. A single day of ethanol exposure during development has persistent effects on bi-directional plasticity, N-methyl-d-aspartate receptor function and ethanol sensitivity. Neuroscience, 136: 269–279, 2005.
31.
JanákyR, VargaV, SaransaariP, and OjaSS. Glutathione modulates the receptor-activated calcium influx into cultured rat cerebellar granule cells. Neurosci Lett, 156: 153–157, 1993.
32.
KandelER, DudaiY, and MayfordMR. The molecular and systems biology of memory. Cell, 157: 163–186, 2014.
33.
KeverneEB, PfaffDW, and TabanskyI. Epigenetic changes in the developing brain: effects on behavior. Proc Natl Acad Sci U S A, 112: 6789–6795, 2015.
34.
KishidaKT, HoefferCA, HuD, PaoM, HollandSM, and KlannE. Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease. Mol Cell Biol, 26: 5908–5920, 2006.
35.
KishidaKT, PaoM, HollandSM, and KlannE. NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1. J Neurochem, 94: 299–306, 2005.
36.
KöhrG, EckardtS, LüddensH, MonyerH, and SeeburgPH. NMDA receptor channels: subunit-specific potentiation by reducing agents. Neuron, 12: 1031–1040, 1994.
37.
Di MaioR, MastroberardinoPG, HuX, MonteroL, and GreenamyreJT. Pilocapine alters NMDA receptor expression and function in hippocampal neurons: NADPH oxidase and ERK1/2 mechanisms. Neurobiol Dis, 42: 482–495, 2011.
38.
MarquardtK and BrigmanJL. The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: insights from rodent models. Alcohol, 51: 1–15, 2016.
39.
MassaadCA and KlannE. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal, 14: 2013–2054, 2011.
40.
MattsonSN, RileyEP, DelisDC, SternC, and JonesKL. Verbal learning and memory in children with fetal alcohol syndrome. Alcohol Clin Exp Res, 20: 810–816, 1996.
MinnellaAM, ZhaoJX, JiangX, JakobsenE, LuF, WuL, El-BennaJ, GrayJA, and SwansonRA. Excitotoxic superoxide production and neuronal death require both ionotropic and non-ionotropic NMDA receptor signaling. Sci Rep, 8: 1–13, 2018.
43.
MorikawaH and MorrisettRA. Ethanol action on dopaminergic neurons in the ventral tegmental area. Int Rev Neurobiol, 91: 235–288, 2010.
44.
MorrisettRA, MartinD, WilsonWA, SavageDD, and SwartzwelderHS. Prenatal exposure to ethanol decreases the sensitivity of the adult rat hippocampus to N-methyl-d-aspartate. Alcohol, 6: 415–420, 1989.
45.
NaassilaM and DaoustM. Effect of prenatal and postnatal ethanol exposure on the developmental profile of mRNAs encoding NMDA receptor subunits in rat hippocampus. J Neurochem, 80: 850–860, 2002.
46.
NisimotoY, JacksonHM, OgawaH, KawaharaT, and LambethJD. Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain. Biochemistry, 49: 2433–2442, 2010.
47.
Nosten-BertrandM, ErringtonML, MurphyKPSJ, TokugawaY, BarboniE, KozlovaE, MichalovichD, MorrisRGM, SilverJ, StewartCL, BlissTVP, and MorrisRJ. Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature, 379: 826–829, 1996.
48.
O'ConnorJJ, RowanMJ, and AnwylR. Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation. Nature, 367: 557–559, 1994.
49.
O'ConnorJJ, RowanMJ, and AnwylR. Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors. J Neurosci, 15: 2013–2020, 1995.
50.
O'LearyCE, ThomasKGF, DodgeNC, MoltenoCD, MeintjesEM, JacobsonJL, and JacobsonSW. Verbal learning and memory impairment in children with fetal alcohol spectrum disorders. Alcohol Clin Exp Res, 39: 724–732, 2015.
51.
De PasqualeR, BeckhauserTF, HernandesMS, and Giorgetti BrittoLR. LTP and LTD in the visual cortex require the activation of NOX2. J Neurosci, 34: 12778–12787, 2014.
52.
PattenAR, BrocardoPS, and ChristieBR. Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure. J Nutr Biochem, 24: 760–769, 2013.
53.
PattenAR, BrocardoPS, SakiyamaC, WortmanRC, NoonanA, Gil-MohapelJ, and ChristieBR. Impairments in hippocampal synaptic plasticity following prenatal ethanol exposure are dependent on glutathione levels. Hippocampus, 23: 1463–1475, 2013.
54.
QueenSA, SanchezCF, LopezSR, PaxtonLL, and SavageDD. Dose- and age-dependent effects of prenatal ethanol exposure on hippocampal metabotropic-glutamate receptor-stimulated phosphoinositide hydrolysis. Alcohol Clin Exp Res, 17: 887–893, 1993.
55.
RichardsonG.Prenatal alcohol and marijuana exposure effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol, 24: 309–320, 2002.
56.
RiquelmeD, AlvarezA, LealN, AdasmeT, EspinozaI, ValdésJA, TroncosoN, HartelS, HidalgoJ, HidalgoC, and CarrascoMA. High-frequency field stimulation of primary neurons enhances ryanodine receptor-mediated Ca 2+ release and generates hydrogen peroxide, which jointly stimulate NF-κB activity. Antioxid Redox Signal, 14: 1245–1259, 2011.
57.
Rodriguez-MunozM and GarzonJ. Nitric oxide and zinc-mediated protein assemblies involved in mu opioid receptor signaling. Mol Neurobiol, 48: 769–782, 2013.
58.
Samudio-RuizSL, AllanAM, ValenzuelaCF, Perrone-BizzozeroNI, and CaldwellKK. Prenatal ethanol exposure persistently impairs NMDA receptor-dependent activation of extracellular signal-regulated kinase in the mouse dentate gyrus. J Neurochem, 109: 1311–1323, 2009.
59.
SanhuezaM, Fernandez-VillalobosG, SteinIS, KasumovaG, ZhangP, BayerKU, OtmakhovN, HellJW, and LismanJ. Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J Neurosci, 31: 9170–9178, 2011.
60.
SavageDD, MontanoCY, OteroMA, and PaxtonLL. Prenatal ethanol exposure decreases hippocampal NMDA-sensitive [3H]-glutamate binding site density in 45-day-old rats. Alcohol, 8: 193–201, 1991.
SickmannHM, PattenAR, MorchK, SawchukS, ZhangC, PartonR, SzlavikL, and ChristieBR. Prenatal ethanol exposure has sex-specific effects on hippocampal long-term potentiation. Hippocampus, 24: 54–64, 2014.
63.
SorceS, SchiavoneS, TucciP, ColaiannaM, JaquetV, CuomoV, Dubois-DauphinM, TrabaceL, and KrauseKH. The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses. J Neurosci, 30: 11317–11325, 2010.
64.
StolkJ, HiltermannTJ, DijkmanJH, and VerhoevenAJ. Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Biol, 11: 95–102, 1994.
65.
SubramoneyS, EastmanE, AdnamsC, SteinDJ, and DonaldKA. The early developmental outcomes of prenatal alcohol exposure: a review. Front Neurol, 9: 1108, 2018.
66.
SunJ, MingL, ShangF, ShenL, ChenJ, and JinY. Apocynin suppression of NADPH oxidase reverses the aging process in mesenchymal stem cells to promote osteogenesis and increase bone mass. Sci Rep, 5: 18572, 2015.
67.
SutherlandRJ, McDonaldRJ, and SavageDD. Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus, 7: 232–238, 1998.
68.
TammarielloSP, QuinnMT, and EstusS. NADPH oxidase contributes directly to oxidative stress and apoptosis in nerve growth factor-deprived sympathetic neurons. J Neurosci, 20: RC53, 2000.
69.
Tejada-SimonM V, SerranoF, VillasanaLE, KanterewiczBI, WuGY, QuinnMT, and KlannE. Synaptic localization of a functional NADPH oxidase in the mouse hippocampus. Mol Cell Neurosci, 29: 97–106, 2005.
70.
TitternessAK and ChristieBR. Prenatal ethanol exposure enhances NMDAR-dependent long-term potentiation in the adolescent female dentate gyrus. Hippocampus, 22: 69–81, 2012.
71.
TodkarA, GranholmL, AljumahM, NilssonKW, ComascoE, and NylanderI. HPA axis gene expression and DNA methylation profiles in rats exposed to early life stress, adult voluntary ethanol drinking and single housing. Front Mol Neurosci, 8: 90, 2015.
72.
TsienJZ, HuertaPT, and TonegawaS. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell, 87: 1327–1338, 1996.
73.
VallesS, FelipoV, MontoliuC, and GuerriC. Alcohol exposure during brain development reduces 3H-MK-801 binding and enhances metabotropic-glutamate receptor-stimulated phosphoinositide hydrolysis in rat hippocampus. Life Sci, 56: 1373–1383, 1995.
74.
VaraschinRK, AllenNA, RosenbergMJ, ValenzuelaCF, and SavageDD. Prenatal alcohol exposure increases histamine H3 receptor-mediated inhibition of glutamatergic neurotransmission in rat dentate gyrus. Alcohol Clin Exp Res, 42: 295–305, 2018.
75.
WaxmanEA, BaconguisI, LynchDR, and RobinsonMB. N-methyl-d-aspartate receptor-dependent regulation of the glutamate transporter excitatory amino acid carrier 1. J Biol Chem, 282: 17594–17607, 2007.
76.
WellsPG, BhatiaS, DrakeDM, and Miller-PinslerL. Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine. Birth Defects Res Part C Embryo Today Rev, 108: 108–130, 2016.
77.
XuJ, WeiX, GaoF, ZhongX, GuoR, JiY, ZhouX, ChenJ, YaoP, LiuX, and WeiX. NADPH oxidase 2 derived ROS contributes to LTP of C-fiber evoked field potentials in spinal dorsal horn and persistent mirror-image pain following high frequency stimulus of the sciatic nerve. Pain, 1: [Epub ahead of print]; DOI: 10.1097/j.pain.0000000000001761, 2019.
78.
ZielonkaJ, ChengG, ZielonkaM, GaneshT, SunA, JosephJ, MichalskiR, O'BrienWJ, LambethJD, and KalyanaramanB. High-throughput assays for superoxide and hydrogen peroxide. J Biol Chem, 289: 16176–16189, 2014.
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