New Interneurons in the Adult Neocortex: Small, Sparse, but Significant?

  • Heather A. Cameron
    Address reprint requests to Heather Cameron, Ph.D., Unit on Neuroplasticity, Mood and Anxiety Disorders Program, NIMH/NIH, Building 35/3C915 MSC 3718, 35 Lincoln Drive, Bethesda, MD 20892
    Unit on Neuroplasticity, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
    Search for articles by this author
  • Alexandre G. Dayer
    Department of Adult Psychiatry, Centre Médical Universitaire, Geneva, Switzerland.
    Search for articles by this author
Published:December 07, 2007DOI:
      During the last decade, the intense study of adult hippocampal neurogenesis has led to several new lines of inquiry in the field of psychiatry. Although it is generally believed that adult mammalian neurogenesis is restricted to the hippocampus and olfactory bulb, a growing number of studies have described new neurons in the adult neocortex in both rodents and nonhuman primates. Interestingly, all of the new neurons observed in these studies have features of interneurons rather than pyramidal cells, the largest neuronal population of the neocortex. In this review, we discuss features of these interneurons that may explain why cortical neurogenesis has been so difficult to detect. In addition, these features suggest ways that production of even a small numbers of new neurons in the adult cortex could make a significant impact on neocortical function.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Altman J.
        Are new neurons formed in the brains of adult mammals?.
        Science. 1962; 135: 1127-1128
        • Kaplan M.S.
        Neurogenesis in the 3-month-old rat visual cortex.
        J Comp Neurol. 1981; 195: 323-338
        • Bernier P.J.
        • Bedard A.
        • Vinet J.
        • Levesque M.
        • Parent A.
        Newly generated neurons in the amygdala and adjoining cortex of adult primates.
        Proc Natl Acad Sci U S A. 2002; 99: 11464-11469
        • Runyan C.A.
        • Shannon Weickert C.
        • Saunders R.C.
        Adult neurogenesis and immediate early gene response to working memory stimulation in the primate prefrontal cortex.
        Society for Neuroscience, Atlanta, GA2006 (Program No. 318.10. 2006 Neuroscience Meeting Planner. October 14–18.)
        • Dayer A.G.
        • Cleaver K.M.
        • Abouantoun T.
        • Cameron H.A.
        New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors.
        J Cell Biol. 2005; 168: 415-427
        • Gould E.
        • Reeves A.J.
        • Graziano M.S.
        • Gross C.G.
        Neurogenesis in the neocortex of adult primates.
        Science. 1999; 286: 548-552
        • Gould E.
        • Vail N.
        • Wagers M.
        • Gross C.G.
        Adult-generated hippocampal and neocortical neurons in macaques have a transient existence.
        Proc Natl Acad Sci U S A. 2001; 98: 10910-10917
        • Kornack D.R.
        • Rakic P.
        Cell proliferation without neurogenesis in adult primate neocortex.
        Science. 2001; 294: 2127-2130
        • Bhardwaj R.D.
        • Curtis M.A.
        • Spalding K.L.
        • Buchholz B.A.
        • Fink D.
        • Bjork-Eriksson T.
        • et al.
        Neocortical neurogenesis in humans is restricted to development.
        Proc Natl Acad Sci U S A. 2006; 103: 12564-12568
        • Rakic P.
        Limits of neurogenesis in primates.
        Science. 1985; 227: 1054-1056
        • Koketsu D.
        • Mikami A.
        • Miyamoto Y.
        • Hisatsune T.
        Nonrenewal of neurons in the cerebral neocortex of adult macaque monkeys.
        J Neurosci. 2003; 23: 937-942
        • Huang L.
        • DeVries G.J.
        • Bittman E.L.
        Photoperiod regulates neuronal bromodeoxyuridine labeling in the brain of a seasonally breeding mammal.
        J Neurobiol. 1998; 36: 410-420
        • Ehninger D.
        • Kempermann G.
        Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex.
        Cereb Cortex. 2003; 13: 845-851
        • Madsen T.M.
        • Treschow A.
        • Bengzon J.
        • Bolwig T.G.
        • Lindvall O.
        • Tingstrom A.
        Increased neurogenesis in a model of electroconvulsive therapy.
        Biol Psychiatry. 2000; 47: 1043-1049
        • Chen J.
        • Magavi S.S.
        • Macklis J.D.
        Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice.
        Proc Natl Acad Sci U S A. 2004; 101: 16357-16362
        • Gu W.
        • Brannstrom T.
        • Wester P.
        Cortical neurogenesis in adult rats after reversible photothrombotic stroke.
        J Cereb Blood Flow Metab. 2000; 20: 1166-1173
        • Jiang W.
        • Gu W.
        • Brannstrom T.
        • Rosqvist R.
        • Wester P.
        Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion.
        Stroke. 2001; 32: 1201-1207
        • Magavi S.S.
        • Leavitt B.R.
        • Macklis J.D.
        Induction of neurogenesis in the neocortex of adult mice.
        Nature. 2000; 405: 951-955
        • Madsen T.M.
        • Yeh D.D.
        • Valentine G.W.
        • Duman R.S.
        Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex.
        Neuropsychopharmacology. 2005; 30: 27-34
        • Johnston D.
        • Amaral D.G.
        in: Shepherd G.M. The Synaptic Organization of the Brain. 5th ed. Oxford University Press, New York2004: 455-498
        • Shepherd G.M.
        • Chen W.R.
        • Greer C.A.
        Olfactory bulb.
        in: Shepherd G.M. The Synaptic Organization of the Brain. 5th ed. Oxford University Press, New York2004: 165-216
        • Bedard A.
        • Cossette M.
        • Levesque M.
        • Parent A.
        Proliferating cells can differentiate into neurons in the striatum of normal adult monkey.
        Neurosci Lett. 2002; 328: 213-216
        • Luzzati F.
        • De Marchis S.
        • Fasolo A.
        • Peretto P.
        Neurogenesis in the caudate nucleus of the adult rabbit.
        J Neurosci. 2006; 26: 609-621
        • Kobayashi T.
        • Ahlenius H.
        • Thored P.
        • Kobayashi R.
        • Kokaia Z.
        • Lindvall O.
        Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats.
        Stroke. 2006; 37: 2361-2367
        • Kokoeva M.V.
        • Yin H.
        • Flier J.S.
        Neurogenesis in the hypothalamus of adult mice: Potential role in energy balance.
        Science. 2005; 310: 679-683
        • Shechter R.
        • Ziv Y.
        • Schwartz M.
        New GABAergic interneurons supported by myelin-specific T cells are formed in intact adult spinal cord.
        Stem Cells. 2007; 25: 2277-2282
        • Gutierrez R.
        The GABAergic phenotype of the “glutamatergic” granule cells of the dentate gyrus.
        Prog Neurobiol. 2003; 71: 337-358
        • Markram H.
        • Toledo-Rodriguez M.
        • Wang Y.
        • Gupta A.
        • Silberberg G.
        • Wu C.
        Interneurons of the neocortical inhibitory system.
        Nat Rev Neurosci. 2004; 5: 793-807
        • Mullen R.J.
        • Buck C.R.
        • Smith A.M.
        NeuN, a neuronal specific nuclear protein in vertebrates.
        Development. 1992; 116: 201-211
        • Gabbott P.L.
        • Bacon S.J.
        Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey: I.
        J Comp Neurol. 1996; 364: 567-608
        • Wonders C.P.
        • Anderson S.A.
        The origin and specification of cortical interneurons.
        Nat Rev Neurosci. 2006; 7: 687-696
        • Yuste R.
        Origin and classification of neocortical interneurons.
        Neuron. 2005; 48: 524-527
        • Gabbott P.L.
        • Dickie B.G.
        • Vaid R.R.
        • Headlam A.J.
        • Bacon S.J.
        Local-circuit neurones in the medial prefrontal cortex (areas 25, 32 and 24b) in the rat: Morphology and quantitative distribution.
        J Comp Neurol. 1997; 377: 465-499
        • Brandt M.D.
        • Jessberger S.
        • Steiner B.
        • Kronenberg G.
        • Reuter K.
        • Bick-Sander A.
        • et al.
        Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.
        Mol Cell Neurosci. 2003; 24: 603-613
        • Jones E.G.
        Neurogliaform or spiderweb cells.
        in: Peters A. Jones E.G. Cerebral Cortex. Vol. 1. Plenum Press, New York1984: 409-418
        • Ramón y Cajal S.
        Histology of the Nervous System of Man and Vertebrates.
        Oxford University Press, New York1995
        • Simon A.
        • Olah S.
        • Molnar G.
        • Szabadics J.
        • Tamas G.
        Gap-junctional coupling between neurogliaform cells and various interneuron types in the neocortex.
        J Neurosci. 2005; 25: 6278-6285
        • Szabadics J.
        • Tamas G.
        • Soltesz I.
        Spill-over of GABA after single action potential of neurogliaform cells results in slow postsynaptic GABAA responses.
        Society for Neuroscience, Atlanta, GA2006 (Program 318.10. 2006 Neuroscience Meeting Planner. October 14–18.)
        • Tamas G.
        • Lorincz A.
        • Simon A.
        • Szabadics J.
        Identified sources and targets of slow inhibition in the neocortex.
        Science. 2003; 299: 1902-1905
        • Dawson M.R.
        • Polito A.
        • Levine J.M.
        • Reynolds R.
        NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS.
        Mol Cell Neurosci. 2003; 24: 476-488
        • Tamura Y.
        • Kataoka Y.
        • Cui Y.
        • Takamori Y.
        • Watanabe Y.
        • Yamada H.
        Multi-directional differentiation of doublecortin- and NG2-immunopositive progenitor cells in the adult rat neocortex in vivo.
        Eur J Neurosci. 2007; 25: 3489-3498
        • He W.
        • Ingraham C.
        • Rising L.
        • Goderie S.
        • Temple S.
        Multipotent stem cells from the mouse basal forebrain contribute GABAergic neurons and oligodendrocytes to the cerebral cortex during embryogenesis.
        J Neurosci. 2001; 21: 8854-8862
        • Petryniak M.A.
        • Potter G.B.
        • Rowitch D.H.
        • Rubenstein J.L.
        Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain.
        Neuron. 2007; 55: 417-433
        • Aguirre A.A.
        • Chittajallu R.
        • Belachew S.
        • Gallo V.
        NG2-expressing cells in the subventricular zone are type C-like cells and contribute to interneuron generation in the postnatal hippocampus.
        J Cell Biol. 2004; 165: 575-589
        • Belachew S.
        • Chittajallu R.
        • Aguirre A.A.
        • Yuan X.
        • Kirby M.
        • Anderson S.
        • et al.
        Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons.
        J Cell Biol. 2003; 161: 169-186
        • Chittajallu R.
        • Aguirre A.
        • Gallo V.
        NG2-positive cells in the mouse white and grey matter display distinct physiological properties.
        J Physiol. 2004; 561: 109-122
        • Ganat Y.M.
        • Silbereis J.
        • Cave C.
        • Ngu H.
        • Anderson G.M.
        • Ohkubo Y.
        • et al.
        Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo.
        J Neurosci. 2006; 26: 8609-8621
        • Nacher J.
        • Crespo C.
        • McEwen B.S.
        Doublecortin expression in the adult rat telencephalon.
        Eur J Neurosci. 2001; 14: 629-644
        • Leuner B.
        • Gould E.
        • Shors T.J.
        Is there a link between adult neurogenesis and learning?.
        Hippocampus. 2006; 16: 216-224
        • Cameron H.A.
        • Christie B.R.
        Do new neurons have a functional role in the adult hippocampus?.
        Debates Neurosci. 2007; 1: 26-32
        • Olariu A.
        • Cleaver K.M.
        • Shore L.E.
        • Brewer M.D.
        • Cameron H.A.
        A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus.
        Hippocampus. 2005; 15: 750-762
        • Dayer A.G.
        • Ford A.A.
        • Cleaver K.M.
        • Yassaee M.
        • Cameron H.A.
        Short-term and long-term survival of new neurons in the rat dentate gyrus.
        J Comp Neurol. 2003; 460: 563-572
        • Somogyi P.
        • Klausberger T.
        Defined types of cortical interneurone structure space and spike timing in the hippocampus.
        J Physiol. 2005; 562: 9-26
        • Thom M.
        • Holton J.L.
        • D’Arrigo C.
        • Griffin B.
        • Beckett A.
        • Sisodiya S.
        • et al.
        Microdysgenesis with abnormal cortical myelinated fibres in temporal lobe epilepsy: A histopathological study with calbindin D-28-K immunohistochemistry.
        Neuropathol Appl Neurobiol. 2000; 26: 251-257
        • Rajkowska G.
        Cell pathology in mood disorders.
        Semin Clin Neuropsychiatry. 2002; 7: 281-292
        • Banasr M.
        • Valentine G.W.
        • Li X.Y.
        • Gourley S.L.
        • Taylor J.R.
        • Duman R.S.
        Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat.
        Biol Psychiatry. 2007; 62: 496-504
        • Alonso G.
        Prolonged corticosterone treatment of adult rats inhibits the proliferation of oligodendrocyte progenitors present throughout white and gray matter regions of the brain.
        Glia. 2000; 31: 219-231
        • Czeh B.
        • Muller-Keuker J.I.
        • Rygula R.
        • Abumaria N.
        • Hiemke C.
        • Domenici E.
        • et al.
        Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: Hemispheric asymmetry and reversal by fluoxetine treatment.
        Neuropsychopharmacology. 2007; 32: 1490-1503
        • Korbo L.
        • Pakkenberg B.
        • Ladefoged O.
        • Gundersen H.J.
        • Arlien-Soborg P.
        • Pakkenberg H.
        An efficient method for estimating the total number of neurons in rat brain cortex.
        J Neurosci Methods. 1990; 31: 93-100
        • West M.J.
        • Andersen A.H.
        An allometric study of the area dentata in the rat and mouse.
        Brain Res. 1980; 2: 317-348