Abstract
Selective serotonin reuptake inhibitor (SSRI)-type antidepressants are often prescribed to depressive pregnant women for their less adverse side effects. However, growing evidences have shown increased congenital malformations and poor neonatal adaptation in the perinatal SSRI-exposed human infants as well as animal pups. In this study, we examined the effects of early exposure of fluoxetine, the most popular SSRI-type antidepressant, on the developing somatosensory system. Physiological saline or fluoxetine (10 mg/kg) was subcutaneously injected into neonatal rats from P0 to P6. Somatosensory-related behaviors were examined in adolescence (P30–P35). Morphological features of the primary somatosensory cortex were checked at P7 and P35. The tactile and thermal perceptions as well as locomotor activity were affected by neonatal fluoxetine treatment. At the morphological level, the number of branch tips of thalamocortical afferents to the somatosensory cortex was reduced in the fluoxetine-treated rats. Furthermore, the spiny stellate neurons in the layer IV somatosensory cortex had reduced dendritic span and complexity with fewer branches, shorter dendritic length, and smaller dendritic field. The spine density of spiny stellate neurons was significantly reduced whereas the spine length of mushroom- and branched-type was increased. Taken together, these results indicate that neonatal fluoxetine administration has long-lasting effects on the function and structure in the somatosensory system. Sensory information processing may be disturbed in the neonatal fluoxetine-treated animals due to the structural deformation in the thalamocortical afferents and dendritic structures of the spiny stellate neurons in the layer IV somatosensory cortex.
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References
Ansorge MS, Morelli E, Gingrich JA (2008) Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 28:199–207
Baloyannis SJ, Costa V, Mauroudis I, Psaroulis D, Manolides SL, Manolides LS (2007) Dendritic and spinal pathology in the acoustic cortex in Alzheimer’s disease: morphological and morphometric estimation by Golgi technique and electron microscopy. Acta Otolaryngol 127:351–354
Bar-Oz B, Einarson T, Einarson A, Boskovic R, O’Brien L, Malm H, Bérard A, Koren G (2007) Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 29:918–926
Baumann P, Rochat B (1995) Comparative pharmacokinetics of selective serotonin reuptake inhibitors: a look behind the mirror. Int Clin Psychopharmacol 10(Suppl 1):15–21
Bennett-Clarke CA, Leslie MJ, Chiaia NL, Rhoades RW (1993) Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Proc Natl Acad Sci USA 90:153–157
Bennett-Clarke CA, Chiaia NL, Rhoades RW (1996) Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites. Brain Res 733:301–306
Blazer DG, Kessler RC, McGonagle KA, Swartz MS (1994) The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry 151:979–986
Borue X, Chen J, Condron BG (2007) Developmental effects of SSRIs: lessons learned from animal studies. Int J Dev Neurosci 25:341–347
Bou-Flores C, Lajard AM, Monteau R, De Maeyer E, Seif I, Lanoir J, Hilaire G (2000) Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess. J Neurosci 20:4646–4656
Brecht M (2007) Barrel cortex and whisker-mediated behaviors. Curr Opin Neurobiol 17:408–416
Brezun JM, Daszuta A (2000) Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 12:391–396
Butkevich IP, Khozhai LI, Mikhailenko VA, Otellin VA (2003) Decreased serotonin level during pregnancy alters morphological and functional characteristics of tonic nociceptive system in juvenile offspring of the rat. Reprod Biol Endocrinol 1:96
Calabrese B, Wilson MS, Halpain S (2006) Development and regulation of dendritic spine synapses. Physiology (Bethesda) 21:38–47
Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P (1996) Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16:297–307
Celikel T, Sakmann B (2007) Sensory integration across space and in time for decision making in the somatosensory system of rodents. Proc Natl Acad Sci USA 104:1395–1400
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL (1996) Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 335:1010–1015
Datwani A, Iwasato T, Itohara S, Erzurumlu RS (2002) NMDA receptor-dependent pattern transfer from afferents to postsynaptic cells and dendritic differentiation in the barrel cortex. Mol Cell Neurosci 21:477–492
Debski EA, Cline HT (2002) Activity-dependent mapping in the retinotectal projection. Curr Opin Neurobiol 12:93–99
Diamond ME, von Heimendahl M, Knutsen PM, Kleinfeld D, Ahissar E (2008) ‘Where’ and ‘what’ in the whisker sensorimotor system. Nat Rev Neurosci 9:601–612
Erzurumlu RS, Kind PC (2001) Neural activity: sculptor of ‘barrels’ in the neocortex. Trends Neurosci 24:589–595
Esaki T, Cook M, Shimoji K, Murphy DL, Sokoloff L, Holmes A (2005) Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice. Proc Natl Acad Sci USA 102:5582–5587
Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Brain Res Rev 39:29–54
Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012
Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57:65–73
Groc L, Petanjek Z, Gustafsson B, Ben-Ari Y, Hanse E, Khazipov R (2002) In vivo blockade of neural activity alters dendritic development of neonatal CA1 pyramidal cells. Eur J Neurosci 16:1931–1938
Hannan AJ, Blakemore C, Katsnelson A, Vitalis T, Huber KM, Bear M, Roder J, Kim D, Shin HS, Kind PC (2001) PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nat Neurosci 4:282–288
Holmes A, Lit Q, Murphy DL, Gold E, Crawley JN (2003) Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2:365–380
Hutson KA, Masterton RB (1986) The sensory contribution of a single vibrissa’s cortical barrel. J Neurophysiol 56:1196–1223
Inan M, Crair MC (2007) Development of cortical maps: perspectives from the barrel cortex. Neuroscientist 13:49–61
Iwasato T, Datwani A, Wolf AM, Nishiyama H, Taguchi Y, Tonegawa S, Knöpfel T, Erzurumlu RS, Itohara S (2000) Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406:726–731
Källén B (2004) Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 158:312–316
Kalueff AV, Jensen CL, Murphy DL (2007) Locomotory patterns, spatiotemporal organization of exploration and spatial memory in serotonin transporter knockout mice. Brain Res 1169:87–97
Kaufmann WE, Moser HW (2000) Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 10:981–991
Kesterson KL, Lane RD, Rhoades RW (2002) Effects of elevated serotonin levels on patterns of GAP-43 expression during barrel development in rat somatosensory cortex. Brain Res Dev Brain Res 139:167–174
Khelfaoui M, Denis C, van Galen E, de Bock F, Schmitt A, Houbron C, Morice E, Giros B, Ramakers G, Fagni L, Chelly J, Nosten-Bertrand M, Billuart P (2007) Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J Neurosci 27:9439–9450
Knobloch M, Mansuy IM (2008) Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Mol Neurobiol 37:73–82
Laine K, Heikkinen T, Ekblad U, Kero P (2003) Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60:720–726
Laurent A, Goaillard JM, Cases O, Lebrand C, Gaspar P, Ropert N (2002) Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice. J Neurosci 22:886–900
Lebrand C, Cases O, Adelbrecht C, Doye A, Alvarez C, El Mestikawy S, Seif I, Gaspar P (1996) Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17:823–835
Lebrand C, Cases O, Wehrlé R, Blakely RD, Edwards RH, Gaspar P (1998) Transient developmental expression of monoamine transporters in the rodent forebrain. J Comp Neurol 401(4):506–524
Lebrand C, Gaspar P, Nicolas D, Hornung JP (2006) Transitory uptake of serotonin in the developing sensory pathways of the common marmoset. J Comp Neurol 499:677–689
Lee LJ, Iwasato T, Itohara S, Erzurumlu RS (2005a) Exuberant thalamocortical axon arborization in cortex-specific NMDAR1 knockout mice. J Comp Neurol 485:280–292
Lee LJ, Lo FS, Erzurumlu RS (2005b) NMDA receptor-dependent regulation of axonal and dendritic branching. J Neurosci 25:2304–2311
Lisboa SF, Oliveira PE, Costa LC, Venâncio EJ, Moreira EG (2007) Behavioral evaluation of male and female mice pups exposed to fluoxetine during pregnancy and lactation. Pharmacology 80:49–56
Lu HC, Butts DA, Kaeser PS, She WC, Janz R, Crair MC (2006) Role of efficient neurotransmitter release in barrel map development. J Neurosci 26:2692–2703
Lübke J, Egger V, Sakmann B, Feldmeyer D (2000) Columnar organization of dendrites and axons of single and synaptically coupled excitatory spiny neurons in layer 4 of the rat barrel cortex. J Neurosci 20:5300–5311
Luo X, Persico AM, Lauder JM (2003) Serotonergic regulation of somatosensory cortical development: lessons from genetic mouse models. Dev Neurosci 25:173–183
Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA (2006) Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology 31:47–57
Mansour-Robaey S, Mechawar N, Radja F, Beaulieu C, Descarries L (1998) Quantified distribution of serotonin transporter and receptors during the postnatal development of the rat barrel field cortex. Brain Res Dev Brain Res 107:159–163
McKinney BC, Grossman AW, Elisseou NM, Greenough WT (2005) Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 136B:98–102
Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474
Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL (2005) Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 293:2372–2383
Muñoz A, Liu XB, Jones EG (1999) Development of metabotropic glutamate receptors from trigeminal nuclei to barrel cortex in postnatal mouse. J Comp Neurol 409:549–566
Nelson LS, Erdman AR, Booze LL, Cobaugh DJ, Chyka PA, Woolf AD, Scharman EJ, Wax PM, Manoguerra AS, Christianson G, Caravati EM, Troutman WG (2007) Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 45:315–332
Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP (2008) Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities. PLoS ONE 3:e2782
Norrholm SD, Ouimet CC (2000) Chronic fluoxetine administration to juvenile rats prevents age-associated dendritic spine proliferation in hippocampus. Brain Res 883:205–215
Oberlander TF, Grunau RE, Fitzgerald C, Papsdorf M, Rurak D, Riggs W (2005) Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure. Pediatrics 115:411–425
Persico AM, Mengual E, Moessner R, Hall FS, Revay RS, Sora I, Arellano J, DeFelipe J, Gimenez-Amaya JM, Conciatori M, Marino R, Baldi A, Cabib S, Pascucci T, Uhl GR, Murphy DL, Lesch KP, Keller F (2001) Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci 21:6862–6873
Petersen CC (2007) The functional organization of the barrel cortex. Neuron 56:339–355
Purpura DP (1974) Dendritic spine “dysgenesis” and mental retardation. Science 186:1126–1128
Rebsam A, Seif I, Gaspar P (2002) Refinement of thalamocortical arbors and emergence of barrel domains in the primary somatosensory cortex: a study of normal and monoamine oxidase a knock-out mice. J Neurosci 22:8541–8552
Rhoades RW, Bennett-Clarke CA, Shi MY, Mooney RD (1994) Effects of 5-HT on thalamocortical synaptic transmission in the developing rat. J Neurophysiol 72:2438–2450
Romijn HJ, Hofman MA, Gramsbergen A (1991) At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev 26:61–67
Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer E, Murphy DL, Mossner R, Lesch KP, Hen R, Seif I (2001) Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice. J Neurosci 21:884–896
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R (2005) Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 365:482–487
Schmidt JT (2004) Activity-driven sharpening of the retinotectal projection: the search for retrograde synaptic signaling pathways. J Neurobiol 59:114–133
Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406
Silva-Gómez AB, Rojas D, Juárez I, Flores G (2003) Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res 983:128–136
Sommer C (2004) Serotonin in pain and analgesia: actions in the periphery. Mol Neurobiol 30:117–125
Sorra KE, Harris KM (2000) Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus 10:501–511
Spires TL, Molnár Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ (2005) Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb Cortex 15:385–393
Svensson CI, Tran TK, Fitzsimmons B, Yaksh TL, Hua XY (2006) Descending serotonergic facilitation of spinal ERK activation and pain behavior. FEBS Lett 580:6629–6634
Swann JW, Al-Noori S, Jiang M, Lee CL (2000) Spine loss and other dendritic abnormalities in epilepsy. Hippocampus 10:617–625
Van den Hove DL, Blanco CE, Scheepens A, Desbonnet L, Myint AM, Leonard BE, Prickaerts J, Steinbusch HW (2008) Prenatal maternal paroxetine treatment and neonatal mortality in the rat: a preliminary study. Neonatology 93:52–55
Ververs T, Kaasenbrood H, Visser G, Schobben F, de Jong-van den Berg L, Egberts T (2006) Prevalence and patterns of antidepressant drug use during pregnancy. Eur J Clin Pharmacol 62:863–870
Vitalis T, Cases O, Callebert J, Launay JM, Price DJ, Seif I, Gaspar P (1988) Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period. J Comp Neurol 393:169–184
Vogel C, Mössner R, Gerlach M, Heinemann T, Murphy DL, Riederer P, Lesch KP, Sommer C (2003) Absence of thermal hyperalgesia in serotonin transporter-deficient mice. J Neurosci 23:708–715
Wang JW, David DJ, Monckton JE, Battaglia F, Hen R (2008) Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 28:1374–1384
Woolsey TA, Van der Loos H (1970) The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17:205–242
Xu Y, Sari Y, Zhou FC (2004) Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development. Brain Res Dev Brain Res 150:151–161
Young-Davies CL, Bennett-Clarke CA, Lane RD, Rhoades RW (2000) Selective facilitation of the serotonin(1B) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat. J Comp Neurol 425:130–138
Acknowledgments
This work was supported by National Science Council of the Republic of China (Grant No. NSC 96-2628-B-002-053-MY3). The author thanks Drs. R.S. Erzurumlu and F.-C. Zhou for helpful comments on the manuscript and Mr. Y.-C. Wang for technical assistance.
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Lee, LJ. Neonatal Fluoxetine Exposure Affects the Neuronal Structure in the Somatosensory Cortex and Somatosensory-Related Behaviors in Adolescent Rats. Neurotox Res 15, 212–223 (2009). https://doi.org/10.1007/s12640-009-9022-4
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DOI: https://doi.org/10.1007/s12640-009-9022-4