Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d-aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain.
AkhmetshinaDNasretdinovAZakharovAValeevaGKhazipovR.2016. The nature of the sensory input to the neonatal rat barrel cortex. J Neurosci36(38):9922–32.
2.
AlleneCCattaniAAckmanJBBonifaziPAniksztejnLBen-AriY, and others. 2008. Sequential generation of two distinct synapse-driven network patterns in developing neocortex. J Neurosci28(48):12851–63.
3.
Bauer-MoffettCAltmanJ.1977. The effect of ethanol chronically administered to preweanling rats on cerebellar development: a morphological study. Brain Res119(2):249–68.
4.
Ben-AriYCherubiniECorradettiRGaiarsaJ-L.1989. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol416:303–25.
5.
BittigauPSifringerMGenzKReithEPospischilDGovindarajaluS, and others. 2002. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A99(23):15089–94.
BoleaSAvignoneEBerrettaNSanchez-AndresJVCherubiniE.1999. Glutamate controls the induction of GABA-mediated giant depolarizing potentials through AMPA receptors in neonatal rat hippocampal slices. J Neurophysiol81(5):2095–102.
8.
ChernovaKBurkhanovaGZakharovAKhazipovRSitdikovaG.2017. Inhibitory effects of ethanol in the neonatal rat hippocampus in vivo. BioNanoScience7:159.
9.
ColonneseMTKhazipovR.2010. “Slow activity transients” in infant rat visual cortex: a spreading synchronous oscillation patterned by retinal waves. J Neurosci30(12):4325–37.
10.
ColonneseMKhazipovR.2012. Spontaneous activity in developing sensory circuits: Implications for resting state fMRI. Neuroimage62(4):2212–21.
11.
CreeleyCEOlneyJW. 2013. Drug-induced apoptosis: mechanism by which alcohol and many other drugs can disrupt brain development. Brain Sci3(3):1153–81.
12.
DawMIAshbyMCIsaacJT. 2007. Coordinated developmental recruitment of latent fast spiking interneurons in layer IV barrel cortex. Nat Neurosci10(4):453–61.
13.
DikranianKQinYQLabruyereJNemmersBOlneyJW. 2005. Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures. Dev Brain Res155(1):1–13.
14.
DildymayfieldJEHarrisRA. 1995. Ethanol inhibits kainate responses of glutamate receptors expressed in xenopus oocytes—role of calcium and protein-kinase-C. J Neurosci15(4):3162–71.
15.
DuntyWCJrChenSYZuckerRMDehartDBSulikKK. 2001. Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: implications for alcohol-related birth defects and neurodevelopmental disorder. Alcohol Clin Exp Res25(10):1523–35.
16.
DupontEHanganuILKilbWHirschSLuhmannHJ. 2006. Rapid developmental switch in the mechanisms driving early cortical columnar networks. Nature439(7072):79–83.
17.
DzhalaVITalosDMSdrullaDABrumbackACMathewsGCBenkeTA, and others. 2005. NKCC1 transporter facilitates seizures in the developing brain. Nat Med11(11):1205–13.
18.
FarberNBOlneyJW. 2003. Drugs of abuse that cause developing neurons to commit suicide. Dev Brain Res147(1–2):37–45.
19.
GalindoRZamudioPAValenzuelaCF. 2005. Alcohol is a potent stimulant of immature neuronal networks: implications for fetal alcohol spectrum disorder. J Neurochem94(6):1500–11.
20.
GiraultVGilardVMarguetFLesueurCHauchecorneMRamdaniY, and others. 2017. Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels. Cell Death Dis8(2):e2610.
21.
GolbsANimmervollBSunJJSavaIELuhmannHJ. 2011. Control of programmed cell death by distinct electrical activity patterns. Cereb Cortex21(5):1192–202.
22.
GolshaniPJonesEG. 1999. Synchronized paroxysmal activity in the developing thalamocortical network mediated by corticothalamic projections and “silent” synapses. J Neurosci19(8):2865–75.
23.
HagenstonAMBadingH.2011. Calcium signaling in synapse-to-nucleus communication. Cold Spring Harb Perspect Biol3(11):a004564.
24.
HanganuILBen AriYKhazipovR.2006. Retinal waves trigger spindle bursts in the neonatal rat visual cortex. J Neurosci26(25):6728–36.
25.
Hanganu-OpatzIL2010. Between molecules and experience: role of early patterns of coordinated activity for the development of cortical maps and sensory abilities. Brain Res Rev64(1):160–76.
26.
HarrisRA.1999. Ethanol actions on multiple ion channels: which are important?Alcohol Clin Exp Res23(10):1563–70.
27.
HeckNGolbsARiedemannTSunJJLessmannVLuhmannHJ. 2008. Activity-dependent regulation of neuronal apoptosis in neonatal mouse cerebral cortex. Cereb Cortex. 18(6):1335–49.
IkonomidouC. 2009. Triggers of apoptosis in the immature brain. Brain Dev. 31(7):488–92.
30.
IkonomidouCBittigauPIshimaruMJWozniakDFKochCGenzK, and others. 2000. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science287(5455):1056–60.
31.
IkonomidouCBoschFMiksaMBittigauPVöcklerJDikranianK, and others. 1999. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science283(5398):70–4.
32.
InacioARNasretdinovALebedevaJKhazipovR.2016. Sensory feedback synchronizes motor and sensory neuronal networks in the neonatal rat spinal cord. Nat Commun7:13060.
33.
Jevtovic-TodorovicVHartmanREIzumiYBenshoffNDDikranianKZorumskiCF, and others. 2003. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci23(3):876–82.
34.
JégouSEl GhaziFde LendeuPKMarretSLaudenbachVUguenA, and others. 2012. Prenatal alcohol exposure affects vasculature development in the neonatal brain. Ann Neurol72(6):952–60.
35.
KarlssonKAMohnsEJdi PriscoGVBlumbergMS. 2006. On the co-occurrence of startles and hippocampal sharp waves in newborn rats. Hippocampus. 16(11):959–65.
36.
KhalilovIDzhalaVBen-AriYKhazipovR.1999. Dual role of GABA in the neonatal rat hippocampus. Dev Neurosci. 21(3–5):310–9.
37.
KhalilovIMinlebaevMMukhtarovMKhazipovR.2015. Dynamic changes from depolarizing to hyperpolarizing GABAergic actions during giant depolarizing potentials in the neonatal rat hippocampus. J Neurosci35(37):12635–42.
38.
KhazipovRLuhmannHJ. 2006. Early patterns of electrical activity in the developing cerebral cortex of humans and rodents. Trends Neurosci29(7):414–8.
39.
KhazipovRMinlebaevMValeevaG.2013. Early gamma oscillations. Neuroscience250:240–52.
40.
KhazipovRSirotaALeinekugelXHolmesGLBen AriYBuzsakiG.2004. Early motor activity drives spindle bursts in the developing somatosensory cortex. Nature432(7018):758–61.
41.
KiddFLIsaacJT. 1999. Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses. Nature400(6744):569–73.
42.
KilbWKirischukSLuhmannHJ. 2011. Electrical activity patterns and the functional maturation of the neocortex. Eur J Neurosci34(10):1677–86.
43.
KilbWKirischukSLuhmannHJ. 2013. Role of tonic GABAergic currents during pre- and early postnatal rodent development. Front Neural Circuits7:139.
44.
KirmseKKummerMKovalchukYWitteOWGaraschukOHolthoffK.2015. GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo. Nat Commun6:7750.
45.
LamsaKPalvaJMRuusuvuoriEKailaKTairaT.2000. Synaptic GABA(A) activation inhibits AMPA-kainate receptor-mediated bursting in the newborn (P0-P2) rat hippocampus. J Neurophysiol83(1):359–66.
46.
LebedevaJZakharovAOgievetskyEMinlebaevaAKurbanovRGerasimovaE, and others. 2017. Inhibition of cortical activity and apoptosis caused by ethanol in neonatal rats in vivo. Cereb Cortex27(2):1068–82.
47.
LebedevaYAZakharovaAVSitdikovaGFZefirovALKhazipovRN. 2016. Ketamine-midazolam anesthesia induces total inhibition of cortical activity in the brain of newborn rats. Bull Exp Biol Med161(1):15–19.
48.
LeinekugelXKhazipovRCannonRHiraseHBen AriYBuzsakiG.2002. Correlated bursts of activity in the neonatal hippocampus in vivo. Science296(5575):2049–52.
49.
LeveilleFPapadiaSFrickerMBellKFSorianoFXMartelMA, and others. 2010. Suppression of the intrinsic apoptosis pathway by synaptic activity. J Neurosci30(7):2623–35.
50.
LovingerDMWhiteGWeightFF. 1989. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science243(4899):1721–4.
51.
LuhmannHJSinningAYangJWReyes-PuertaVStuttgenMCKirischukS, and others. 2016. Spontaneous neuronal activity in developing neocortical networks: from single cells to large-scale interactions. Front Neural Circuits. 10:40.
52.
LuoJ. 2012. Mechanisms of ethanol-induced death of cerebellar granule cells. Cerebellum. 11(1):145–54.
MennerickSZorumskiCF. 2000. Neural activity and survival in the developing nervous system. Mol Neurobiol. 22(1–3):41–54.
56.
MinlebaevMBen-AriYKhazipovR.2009. NMDA receptors pattern early activity in the developing barrel cortex in vivo. Cereb Cortex. 19(3):688–96.
57.
MinlebaevMBen-AriYKhazipovR.2007. Network mechanisms of spindle-burst oscillations in the neonatal rat barrel cortex in vivo. J Neurophysiol97(1):692–700.
58.
MinlebaevMColonneseMTsintsadzeTSirotaAKhazipovR.2011. Early gamma oscillations synchronize developing thalamus and cortex. Science334(6053):226–9.
59.
ModyIGlykysJWeiWZ. 2007. A new meaning for “gin & tonic”: tonic inhibition as the target for ethanol action in the brain. Alcohol41(3):145–53.
60.
MohnsEJBlumbergMS. 2010. Neocortical activation of the hippocampus during sleep in infant rats. J Neurosci30(9):3438–49.
61.
MonyerHBurnashevNLaurieDJSakmannBSeeburgPH. 1994. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron12(3):529–40.
62.
MortonRAValenzuelaCF. 2016. Further characterization of the effect of ethanol on voltage-gated Ca2+ channel function in developing CA3 hippocampal pyramidal neurons. Brain Res1633:19–26.
63.
NikolicMGardnerHATuckerKL. 2013. Postnatal neuronal apoptosis in the cerebral cortex: physiological and pathophysiological mechanisms. Neuroscience254:369–78.
64.
NimmervollBWhiteRYangJWAnSMHennCSunJJ, and others. 2013. LPS-induced microglial secretion of TNF alpha increases activity-dependent neuronal apoptosis in the neonatal cerebral cortex. Cereb Cortex23(7):1742–55.
65.
OgievetskyELotfullinaNMinlebaevaAKhazipovR.2016. Ethanol-induced apoptosis of interneurons in the neonatal GAD67-GFP mouse hippocampus. BioNanoScience. Epub Oct. doi:10.1007/s12668-016-0334-6.
66.
OlneyJWTenkovaTDikranianKMugliaLJJermakowiczWJD’SaC, and others. 2002a. Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiol Dis9(2):205–19.
67.
OlneyJWTenkovaTDikranianKQinYQLabruyereJIkonomidouC.2002b. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Dev Brain Res133(2):115–26.
68.
OlneyJWYoungCWozniakDFJevtovic-TodorovicVIkonomidouC.2004. Do pediatric drugs cause developing neurons to commit suicide?Trends Pharmacol Sci25(3):135–9.
69.
OlneyJW. 2014. Focus on apoptosis to decipher how alcohol and many other drugs disrupt brain development. Front Pediatr2:81.
70.
SitdikovaGZakharovAJanackovaSGerasimovaELebedevaJInacioAR, and others. 2014. Isoflurane suppresses early cortical activity. Ann Clin Transl Neurol. 1(1):15–26.
71.
StobbsSHOhranAJLassenMBAllisonDWBrownJESteffensenSC. 2004. Ethanol suppression of ventral tegmental area GABA neuron electrical transmission involves N-methyl-d-aspartate receptors. J Pharmacol Exp Ther311(1):282–9.
72.
TenkovaTYoungCDikranianKLabruyereJOlneyJW. 2003. Ethanol-induced apoptosis in the developing visual system during synaptogenesis. Invest Ophthalmol Vis Sci44(7):2809–17.
TurnerCPDeBenedettoDLiuC.2009. NMDAR blockade-induced neonatal brain injury: reversal by the calcium channel agonist BayK 8644. Neurosci Lett450(3):292–5.
75.
ValeevaGAbdullinATyzioRSkorinkinANikolskiEBen-AriY, and others. 2010. Temporal coding at the immature depolarizing GABAergic synapse. Front Cell Neurosci4.
76.
ValeevaGTressardTMukhtarovMBaudeAKhazipovR.2016. An optogenetic approach for investigation of excitatory and inhibitory network GABA actions in mice expressing channelrhodopsin-2 in GABAergic neurons. J Neurosci36(22):5961–73.
77.
WellsJEPorterJTAgmonA.2000. GABAergic inhibition suppresses paroxysmal network activity in the neonatal rodent hippocampus and neocortex. J Neurosci20(23):8822–30.
78.
WestJRHamreKMCassellMD. 1986. Effects of ethanol exposure during the third trimester equivalent on neuron number in rat hippocampus and dentate gyrus. Alcohol Clin Exp Res10(2):190–7.
79.
WrightJMPeoplesRWWeightFF. 1996. Single-channel and whole-cell analysis of ethanol inhibition of NMDA-activated currents in cultured mouse cortical and hippocampal neurons. Brain Res. 738(2):249–56.
80.
XuWCormierRFuTCoveyDFIsenbergKEZorumskiCF, and others. 2000. Slow death of postnatal hippocampal neurons by GABAA receptor overactivation. J Neurosci20(9):3147–56.
81.
YangJWAnSSunJJReyes-PuertaVKindlerJBergerT, and others. 2013. Thalamic network oscillations synchronize ontogenetic columns in the newborn rat barrel cortex. Cereb Cortex23(6):1299–316.
82.
YangJWHanganu-OpatzILSunJJLuhmannHJ. 2009. Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo. J Neurosci29(28):9011–25.
83.
YoungCKlockeBJTenkovaTChoiJLabruyereJQinYQ, and others. 2003. Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain. Cell Death Differ10(10):1148–55.
84.
YoungCRothKAKlockeBJWestTHoltzmanDMLabruyereJ, and others. 2005. Role of caspase-3 in ethanol-induced developmental neurodegeneration. Neurobiol Dis20(2):608–14.
85.
YoungCLStraikoMMJohnsonSACreeleyCOlneyJW. 2008. Ethanol causes and lithium prevents neuroapoptosis and suppression of pERK in the infant mouse brain. Neurobiol Dis31(3):355–60.
