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Organ der Neurowissenschaftlichen Gesellschaft

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Volume 25, Issue 1


The first cortical circuits: Subplate neurons lead the way and shape cortical organization

Patrick O. Kanold
  • Corresponding author
  • Department of Biology University of Maryland 1116 Biosciences Res. Bldg. College Park, MD 20742 USA Phone: +1 (301) 405.5741 Maryland USA
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Published Online: 2019-02-08 | DOI: https://doi.org/10.1515/nf-2018-0010


The cerebral cortex is essential for our sensory experiences and conscious thought. Its neural connections, in particular sensory areas of the cerebral cortex, are shaped and sculpted by our early sensory experiences. Onset of these first sensory experiences of the world mark an important developmental event, enabling our worldy interactions to shape the makeup of our cerebral cortex. These long-lasting effects of early sensory experience are particularly striking in human communication, since early exposure to the mother’s language is required to detect all nuances in the underlying sounds. Early interactions with the world are mediated by a key set of neurons, subplate neurons, which remain part of the developing cerebral cortex until most of them disappear at later stages of development. They play a crucial role in the developing mammalian brain. Here I review the circuitry and functional roles of cortical subplate neurons, focusing on their purpose in the development of primary sensory cortices.


  • Akerman CJ, Smyth D, Thompson ID (2002) Visual experience before eye-opening and the development of the retinogeniculate pathway. Neuron 36:869–879.Google Scholar

  • Akerman CJ, Grubb MS, Thompson ID (2004) Spatial and temporal properties of visual responses in the thalamus of the developing ferret. J Neurosci 24:170–182.Google Scholar

  • Antonini A, Shatz CJ (1990) Relation Between Putative Transmitter Phenotypes and Connectivity of Subplate Neurons During Cerebral Cortical Development. The European journal of neuroscience 2:744–761.Google Scholar

  • Avino TA, Hutsler JJ (2010) Abnormal cell patterning at the cortical gray-white matter boundary in autism spectrum disorders. Brain research 1360:138–146.Google Scholar

  • Bakken TE et al. (2016) A comprehensive transcriptional map of primate brain development. Nature 535:367–375.Google Scholar

  • Barkat TR, Polley DB, Hensch TK (2011) A critical period for auditory thalamocortical connectivity. Nat Neurosci 14:1189–1194.Google Scholar

  • Bayer L, Serafin M, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Muhlethaler M (2004) Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons. J Neurosci 24:6760–6764.Google Scholar

  • Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, Garcia-Moreno F, Molnar Z, Margulies EH, Ponting CP (2011) A transcriptomic atlas of mouse neocortical layers. Neuron 71:605–616.Google Scholar

  • Birnholz JC, Benacerraf BR (1983) The development of human fetal hearing. Science 222:516–518.Google Scholar

  • Blum T, Saling E, Bauer R (1985) First magnetoencephalographic recordings of the brain activity of a human fetus. Br J Obstet Gynaecol 92:1224–1229.Google Scholar

  • Butts DA, Kanold PO (2010) The applicability of spike time dependent plasticity to development. Front Synaptic Neurosci 2:30.Google Scholar

  • Case L, Broberger C (2017) Neurotensin Broadly Recruits Inhibition via White Matter Neurons in the Mouse Cerebral Cortex: Synaptic Mechanisms for Decorrelation. Cereb Cortex:1–14.Google Scholar

  • Case L, Lyons DJ, Broberger C (2017) Desynchronization of the Rat Cortical Network and Excitation of White Matter Neurons by Neurotensin. Cereb Cortex 27:2671–2685.Google Scholar

  • Chen M, Weng S, Deng Q, Xu Z, He S (2009) Physiological properties of direction-selective ganglion cells in early postnatal and adult mouse retina. The Journal of physiology 587:819–828.Google Scholar

  • Chun JJ, Shatz CJ (1989) The earliest-generated neurons of the cat cerebral cortex: characterization by MAP2 and neurotransmitter immunohistochemistry during fetal life. J Neurosci 9:1648–1667.Google Scholar

  • Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K (2011) Neuron number and size in prefrontal cortex of children with autism. JAMA 306:2001–2010.Google Scholar

  • DeCasper AJ, Fifer WP (1980) Of human bonding: newborns prefer their mothers’ voices. Science 208:1174–1176.Google Scholar

  • Deng R, Kao JPY, Kanold PO (2017) Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex. Cell Rep 19:1141–1150.Google Scholar

  • Draganova R, Eswaran H, Murphy P, Huotilainen M, Lowery C, Preissl H (2005) Sound frequency change detection in fetuses and newborns, a magnetoencephalographic study. Neuroimage 28:354–361.Google Scholar

  • Dupont E, Hanganu IL, Kilb W, Hirsch S, Luhmann HJ (2006) Rapid developmental switch in the mechanisms driving early cortical columnar networks. Nature 439:79–83.Google Scholar

  • Erzurumlu RS, Gaspar P (2012) Development and critical period plasticity of the barrel cortex. The European journal of neuroscience 35:1540–1553.Google Scholar

  • Espinosa JS, Stryker MP (2012) Development and plasticity of the primary visual cortex. Neuron 75:230–249.Google Scholar

  • Estes ML, McAllister AK (2016) Maternal immune activation: Implications for neuropsychiatric disorders. Science 353:772–777.Google Scholar

  • Eswaran H, Lowery CL, Robinson SE, Wilson JD, Cheyne D, McKenzie D (2000) Challenges of recording human fetal auditory-evoked response using magnetoencephalography. J Matern Fetal Med 9:303–307.Google Scholar

  • Eswaran H, Preissl H, Wilson JD, Murphy P, Robinson SE, Rose D, Vrba J, Lowery CL (2002) Short-term serial magnetoencephalography recordings offetal auditory evoked responses. Neuroscience letters 331:128–132.Google Scholar

  • Friauf E, Shatz CJ (1991) Changing patterns of synaptic input to subplate and cortical plate during development of visual cortex. Journal of neurophysiology 66:2059–2071.Google Scholar

  • Friauf E, McConnell SK, Shatz CJ (1990) Functional synaptic circuits in the subplate during fetal and early postnatal development of cat visual cortex. J Neurosci 10:2601–2613.Google Scholar

  • Ghosh A, Shatz CJ (1992a) Involvement of subplate neurons in the formation of ocular dominance columns. Science 255:1441–1443.Google Scholar

  • Ghosh A, Shatz CJ (1992b) Pathfinding and target selection by developing geniculocortical axons. J Neurosci 12:39–55.Google Scholar

  • Ghosh A, Shatz CJ (1993) A role for subplate neurons in the patterning of connections from thalamus to neocortex. Development 117:1031–1047.Google Scholar

  • Ghosh A, Shatz CJ (1994) Segregation of geniculocortical afferents during the critical period: a role for subplate neurons. J Neurosci 14:3862–3880.Google Scholar

  • Ghosh A, Antonini A, McConnell SK, Shatz CJ (1990) Requirement for subplate neurons in the formation of thalamocortical connections. Nature 347:179–181.Google Scholar

  • Hanganu IL, Luhmann HJ (2004) Functional nicotinic acetylcholine receptors on subplate neurons in neonatal rat somatosensory cortex. Journal of neurophysiology 92:189–198.Google Scholar

  • Hanganu IL, Kilb W, Luhmann HJ (2002) Functional synaptic projections onto subplate neurons in neonatal rat somatosensory cortex. J Neurosci 22:7165–7176.Google Scholar

  • Hanganu IL, Okabe A, Lessmann V, Luhmann HJ (2009) Cellular mechanisms of subplate-driven and cholinergic input-dependent network activity in the neonatal rat somatosensory cortex. Cereb Cortex 19:89–105.Google Scholar

  • Hevner RF (2000) Development of connections in the human visual system during fetal mid-gestation: a DiI-tracing study. J Neuropathol Exp Neurol 59:385–392.Google Scholar

  • Higashi S, Molnar Z, Kurotani T, Toyama K (2002) Prenatal development of neural excitation in rat thalamocortical projections studied by optical recording. Neuroscience 115:1231–1246.Google Scholar

  • Hoerder-Suabedissen A, Molnar Z (2013) Molecular diversity of early-born subplate neurons. Cereb Cortex 23:1473–1483.Google Scholar

  • Hoerder-Suabedissen A, Wang WZ, Lee S, Davies KE, Goffinet AM, Rakic S, Parnavelas J, Reim K, Nicolic M, Paulsen O, Molnar Z (2009) Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Cereb Cortex 19:1738–1750.Google Scholar

  • Hoerder-Suabedissen A, Hayashi S, Upton L, Nolan Z, Casas-Torremocha D, Grant E, Viswanathan S, Kanold PO, Clasca F, Kim Y, Molnar Z (2018) Subset of Cortical Layer 6b Neurons Selectively Innervates Higher Order Thalamic Nuclei in Mice. Cereb Cortex.PubMedGoogle Scholar

  • Kanold PO (2009) Subplate neurons: crucial regulators of cortical development and plasticity. Front Neuroanat 3:16.Google Scholar

  • Kanold PO, Shatz CJ (2006) Subplate neurons regulate maturation of cortical inhibition and outcome of ocular dominance plasticity. Neuron 51:627–638.Google Scholar

  • Kanold PO, Luhmann HJ (2010) The subplate and early cortical circuits. Annu Rev Neurosci 33:23–48.Google Scholar

  • Kanold PO, Kara P, Reid RC, Shatz CJ (2003) Role of subplate neurons in functional maturation of visual cortical columns. Science 301:521–525.Google Scholar

  • Kostovic I, Rakic P (1980) Cytology and time of origin of interstitial neurons in the white matter in infant and adult human and monkey telencephalon. J Neurocytol 9:219–242.Google Scholar

  • Kostovic I, Rakic P (1990) Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 297:441–470.Google Scholar

  • Kostovic I, Judas M (2002) Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants. Anat Rec 267:1–6.Google Scholar

  • Kostovic I, Lukinovic N, Judas M, Bogdanovic N, Mrzljak L, Zecevic N, Kubat M (1989) Structural basis of the developmental plasticity in the human cerebral cortex: the role of the transient subplate zone. Metab Brain Dis 4:17–23.Google Scholar

  • Krmpotic-Nemanic J, Kostovic I, Nemanic D, Kelovic Z (1979) The laminar organization of the prospective auditory cortex in the human fetus (11--13.5 weeks of gestation). Acta Otolaryngol 87:241–246.Google Scholar

  • Krug K, Akerman CJ, Thompson ID (2001) Responses of neurons in neonatal cortex and thalamus to patterned visual stimulation through the naturally closed lids. Journal of neurophysiology 85:1436–1443.Google Scholar

  • Lein ES, Finney EM, McQuillen PS, Shatz CJ (1999) Subplate neuron ablation alters neurotrophin expression and ocular dominance column formation. Proceedings of the National Academy of Sciences of the United States of America 96:13491–13495.Google Scholar

  • Lein ES, Belgard TG, Hawrylycz M, Molnar Z (2017) Transcriptomic Perspectives on Neocortical Structure, Development, Evolution, and Disease. Annu Rev Neurosci 40:629–652.Google Scholar

  • Lengle JM, Chen M, Wakai RT (2001) Improved neuromagnetic detection of fetal and neonatal auditory evoked responses. Clin Neurophysiol 112:785–792.Google Scholar

  • Liao CC, Lee LJ (2011) Neonatal fluoxetine exposure affects the action potential properties and dendritic development in cortical subplate neurons of rats. Toxicol Lett 207:314–321.Google Scholar

  • Liao CC, Lee LJ (2012) Evidence for structural and functional changes of subplate neurons in developing rat barrel cortex. Brain Struct Funct 217:275–292.Google Scholar

  • Liao CC, Lee LJ (2014) Presynaptic 5-HT1B receptor-mediated synaptic suppression to the subplate neurons in the somatosensory cortex of neonatal rats. Neuropharmacology 77:81–89.Google Scholar

  • Marx M, Qi G, Hanganu-Opatz IL, Kilb W, Luhmann HJ, Feldmeyer D (2015) Neocortical Layer 6B as a Remnant of the Subplate – A Morphological Comparison. Cereb Cortex.Google Scholar

  • McClendon E, Shaver DC, Degener-O’Brien K, Gong X, Nguyen T, Hoerder-Suabedissen A, Molnar Z, Mohr C, Richardson BD, Rossi DJ, Back SA (2017) Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity. J Neurosci 37:11912–11929.Google Scholar

  • McConnell SK, Ghosh A, Shatz CJ (1989) Subplate neurons pioneer the first axon pathway from the cerebral cortex. Science 245:978–982.Google Scholar

  • McConnell SK, Ghosh A, Shatz CJ (1994) Subplate pioneers and the formation of descending connections from cerebral cortex. J Neurosci 14:1892–1907.Google Scholar

  • McQuillen PS, Ferriero DM (2005) Perinatal subplate neuron injury: implications for cortical development and plasticity. Brain Pathol 15:250–260.Google Scholar

  • McQuillen PS, Sheldon RA, Shatz CJ, Ferriero DM (2003) Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci 23:3308–3315.Google Scholar

  • Mehler J, Jusczyk P, Lambertz G, Halsted N, Bertoncini J, Amiel-Tison C (1988) A precursor of language acquisition in young infants. Cognition 29:143–178.Google Scholar

  • Meng X, Kao JP, Kanold PO (2014) Differential signaling to subplate neurons by spatially specific silent synapses in developing auditory cortex. J Neurosci 34:8855–8864.Google Scholar

  • Mikhailova A, Sunkara N, McQuillen PS (2017) Unbiased Quantification of Subplate Neuron Loss following Neonatal Hypoxia-Ischemia in a Rat Model. Dev Neurosci 39:171–181.Google Scholar

  • Molnar Z, Kaas JH, de Carlos JA, Hevner RF, Lein E, Nemec P (2014) Evolution and development of the mammalian cerebral cortex. Brain Behav Evol 83:126–139.Google Scholar

  • Montiel JF, Wang WZ, Oeschger FM, Hoerder-Suabedissen A, Tung WL, Garcia-Moreno F, Holm IE, Villalon A, Molnar Z (2011) Hypothesis on the dual origin of the Mammalian subplate. Front Neuroanat 5:25.Google Scholar

  • Nagode DA, Meng X, Winkowski DE, Smith E, Khan-Tareen H, Kareddy V, Kao JPY, Kanold PO (2017) Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder. Cell Rep 18:1100–1108.Google Scholar

  • Nelken I (2004) Processing of complex stimuli and natural scenes in the auditory cortex. Curr Opin Neurobiol 14:474–480.Google Scholar

  • Nicolini C, Fahnestock M (2018) The valproic acid-induced rodent model of autism. Exp Neurol 299:217–227.Google Scholar

  • Porcaro C, Zappasodi F, Barbati G, Salustri C, Pizzella V, Rossini PM, Tecchio F (2006) Fetal auditory responses to external sounds and mother’s heart beat: detection improved by Independent Component Analysis. Brain research 1101:51–58.Google Scholar

  • Roullet FI, Lai JK, Foster JA (2013) In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol 36:47–56.Google Scholar

  • Sanes DH, Bao S (2009) Tuning up the developing auditory CNS. Curr Opin Neurobiol 19:188–199.Google Scholar

  • Schleussner E, Schneider U, Kausch S, Kahler C, Haueisen J, Seewald HJ (2001) Fetal magnetoencephalography: a non-invasive method for the assessment of fetal neuronal maturation. BJOG 108:1291–1294.Google Scholar

  • Schneider U, Schleussner E, Haueisen J, Nowak H, Seewald HJ (2001) Signal analysis of auditory evoked cortical fields in fetal magnetoencephalography. Brain Topogr 14:69–80.Google Scholar

  • Sheikh A, Meng X, Liu J, Mikhailova A, Kao JPY, McQuillen PS, Kanold PO (2018) Neonatal Hypoxia-Ischemia Causes Functional Circuit Changes in Subplate Neurons. Cereb Cortex.Google Scholar

  • Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E (2014) Patches of disorganization in the neocortex of children with autism. N Engl J Med 370:1209–1219.Google Scholar

  • Thompson BL, Levitt P, Stanwood GD (2009) Prenatal exposure to drugs: effects on brain development and implications for policy and education. Nature reviews Neuroscience 10:303–312.Google Scholar

  • Tian N, Copenhagen DR (2003) Visual stimulation is required for refinement of ON and OFF pathways in postnatal retina. Neuron 39:85–96.Google Scholar

  • Tolner EA, Sheikh A, Yukin AY, Kaila K, Kanold PO (2012) Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex. J Neurosci 32:692–702.Google Scholar

  • Viswanathan S, Bandyopadhyay S, Kao JP, Kanold PO (2012) Changing microcircuits in the subplate of the developing cortex. J Neurosci 32:1589–1601.Google Scholar

  • Viswanathan S, Sheikh A, Looger LL, Kanold PO (2016) (2017) Molecularly Defined Subplate Neurons Project Both to Thalamocortical Recipient Layers and Thalamus. Cereb Cortex 27:4759–4768.Google Scholar

  • Voegtline KM, Costigan KA, Pater HA, DiPietro JA (2013) Near-term fetal response to maternal spoken voice. Infant Behav Dev 36:526–533.Google Scholar

  • Wakai RT, Leuthold AC, Martin CB (1996) Fetal auditory evoked responses detected by magnetoencephalography. Am J Obstet Gynecol 174:1484–1486.Google Scholar

  • Wang WZ, Oeschger FM, Montiel JF, Garcia-Moreno F, Hoerder-Suabedissen A, Krubitzer L, Ek CJ, Saunders NR, Reim K, Villalon A, Molnar Z (2011) Comparative aspects of subplate zone studied with gene expression in sauropsids and mammals. Cereb Cortex 21:2187–2203.Google Scholar

  • Werner LA (2007) Issues in human auditory development. J Commun Disord 40:275–283.Google Scholar

  • Wess JM, Isaiah A, Watkins PV, Kanold PO (2017) Subplate neurons are the first cortical neurons to respond to sensory stimuli. Proceedings of the National Academy of Sciences of the United States of America 114:12602–12607.Google Scholar

  • Yang JW, Hanganu-Opatz IL, Sun JJ, Luhmann HJ (2009) Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo. J Neurosci 29:9011–9025.Google Scholar

  • Zappasodi F, Tecchio F, Pizzella V, Cassetta E, Romano GV, Filligoi G, Rossini PM (2001) Detection of fetal auditory evoked responses by means of magnetoencephalography. Brain research 917:167–173.Google Scholar

  • Zhao C, Kao JP, Kanold PO (2009) Functional excitatory microcircuits in neonatal cortex connect thalamus and layer 4. J Neurosci 29:15479–15488.Google Scholar

About the article

Patrick O. Kanold

Patrick Kanold is a Professor at the University of Maryland, College Park. He obtained his Dipl.-Ing. in Electrical Engineering at the Technische Universität Berlin 1994; his Ph.D. in Biomedical Engineering from the Johns Hopkins University in Baltimore, USA. From 2000–2006 he was a postdoctoral fellow and Instructor at the Department of Neurobiology at Harvard Medical School in Boston, USA. Since 2007 he is at the University of Maryland College Park, USA.

Published Online: 2019-02-08

Published in Print: 2019-02-07

Citation Information: Neuroforum, Volume 25, Issue 1, Pages 15–23, ISSN (Online) 2363-7013, ISSN (Print) 0947-0875, DOI: https://doi.org/10.1515/nf-2018-0010.

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