Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter April 26, 2014

Emerging evidence of insulin-like growth factor 2 as a memory enhancer: a unique animal model of cognitive dysfunction with impaired adult neurogenesis

Takashi Iwamoto and Yasuo Ouchi


In the current aging society, cognitive dysfunction is one of the most serious issues that should be urgently resolved. It also affects a wide range of age groups harboring neurological and psychiatric disorders, such as Alzheimer’s disease and schizophrenia. Although the molecular mechanism of memory impairment still remains to be determined, neuronal loss and dysfunction has been revealed to mainly attribute to its pathology. The discovery of neural stem cells in the adult brain that are proliferating and able to generate functional neurons has given rise to the idea that neuronal loss could be rescued by manipulating endogenous neural progenitor and stem cells. To this end, we must characterize them in detail and their developmental programming must be better understood. A growing body of evidence has indicated that insulin-like peptides are involved in learning and memory and maintenance of neural progenitor and stem cells, and clinical trials of insulin as a memory enhancer have begun. In contrast to the expectation of insulin and IGF1, the roles of IGF2 in cognitive ability have been poorly understood. However, recent evidence demonstrated in rodents suggests that IGF2 may play a pivotal role in adult neurogenesis and cognitive function. Here, we would like to review the rapidly growing world of IGF2 in cognitive neuroscience and introduce the evidence that its deficit is indeed involved in the impairment of the hippocampal neurogenesis and cognitive dysfunction in the model mouse of 22q11.2 deletion syndrome, which deletes Dgcr8, a critical gene for microRNA processing.

Corresponding author: Takashi Iwamoto, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan, Phone/Fax: +81-568-51-7529, e-mail: ; and The Center for Education in Laboratory Animal Research, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan


The authors would like to thank Yuya Banno and all the laboratory members for technical assistance. The authors have no conflicts of interest relevant to this article.


Agbemenyah, H.Y., Agis-Balboa, R.C., Burkhardt, S., Delalle, I., and Fischer, A. (2014). Insulin growth factor binding protein 7 is a novel target to treat dementia. Neurobiol. Dis. 62, 135–143.10.1016/j.nbd.2013.09.011Search in Google Scholar PubMed

Agis-Balboa, R.C. and Fischer, A. (2014). Generating new neurons to circumvent your fears: the role of IGF signaling. Cell Mol. Life Sci. 71, 21–42.10.1007/s00018-013-1316-2Search in Google Scholar PubMed

Agis-Balboa, R.C., Arcos-Diaz, D., Wittnam, J., Govindarajan, N., Blom, K., Burkhardt, S., Haladyniak, U., Agbemenyah, H.Y., Zovoilis, A., Salinas-Riester, G., et al. (2011). A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J. 30, 4071–4083.10.1038/emboj.2011.293Search in Google Scholar PubMed PubMed Central

Ahn, H.J., Hernandez, C.M., Levenson, J.M., Lubin, F.D., Liou, H.C., and Sweatt, J.D. (2008). c-Rel, an NF-kappaB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation. Learn. Mem. 15, 539–549.10.1101/lm.866408Search in Google Scholar PubMed PubMed Central

Alberini, C.M. and Chen, D.Y. (2012). Memory enhancement: consolidation, reconsolidation and insulin-like growth factor 2. Trends Neurosci. 35, 274–283.10.1016/j.tins.2011.12.007Search in Google Scholar PubMed PubMed Central

Altman, J. and Das, G.D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335.10.1002/cne.901240303Search in Google Scholar PubMed

Arguello, P.A. and Gogos, J.A. (2006). Modeling madness in mice: one piece at a time. Neuron 52, 179–196.10.1016/j.neuron.2006.09.023Search in Google Scholar PubMed

Balu, D.T. and Lucki, I. (2009). Adult hippocampal neurogenesis: regulation, functional implications, and contribution to disease pathology. Neurosci. Biobehav. Rev. 33, 232–252.10.1016/j.neubiorev.2008.08.007Search in Google Scholar PubMed PubMed Central

Balzer, E., Heine, C., Jiang, Q., Lee, V.M., and Moss, E.G. (2010). LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137, 891–900.10.1242/dev.042895Search in Google Scholar PubMed

Beckervordersandforth, R., Tripathi, P., Ninkovic, J., Bayam, E., Lepier, A., Stempfhuber, B., Kirchhoff, F., Hirrlinger, J., Haslinger, A., Lie, D.C., et al. (2010). In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell 7, 744–758.10.1016/j.stem.2010.11.017Search in Google Scholar PubMed

Benoit, C.E., Rowe, W.B., Menard, C., Sarret, P., and Quirion, R. (2011). Genomic and proteomic strategies to identify novel targets potentially involved in learning and memory. Trends Pharmacol. Sci. 32, 43–52.10.1016/ in Google Scholar PubMed

Bernal, G.M. and Peterson, D.A. (2004). stem cells as therapeutic agents for age-related brain repair. Aging Cell 3, 345–351.10.1111/j.1474-9728.2004.00132.xSearch in Google Scholar PubMed

Bieberich, E. (2012). It’s a lipid’s world: bioactive lipid metabolism and signaling in neural stem cell differentiation. Neurochem. Res. 37, 1208–1229.10.1007/s11064-011-0698-5Search in Google Scholar PubMed PubMed Central

Bizon, J.L., Lee, H.J., and Gallagher, M. (2004). Neurogenesis in a rat model of age-related cognitive decline. Aging Cell 3, 227–234.10.1111/j.1474-9728.2004.00099.xSearch in Google Scholar PubMed

Boersma, M.C., Dresselhaus, E.C., De Biase, L.M., Mihalas, A.B., Bergles, D.E., and Meffert, M.K. (2011). A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis. J. Neurosci. 31, 5414–5425.10.1523/JNEUROSCI.2456-10.2011Search in Google Scholar PubMed PubMed Central

Bondy, C.A. and Cheng, C.M. (2004). Signaling by insulin-like growth factor 1 in brain. Eur. J. Pharmacol. 490, 25–31.10.1016/j.ejphar.2004.02.042Search in Google Scholar PubMed

Bracko, O., Singer, T., Aigner, S., Knobloch, M., Winner, B., Ray, J., Clemenson, G.D. Jr., Suh, H., Couillard-Despres, S., Aigner, L., et al. (2012). Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J. Neurosci. 32, 3376–3387.10.1523/JNEUROSCI.4248-11.2012Search in Google Scholar PubMed PubMed Central

Bramham, C.R., Worley, P.F., Moore, M.J., and Guzowski, J.F. (2008). The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J. Neurosci. 28, 11760–11767.10.1523/JNEUROSCI.3864-08.2008Search in Google Scholar PubMed PubMed Central

Breunig, J.J., Silbereis, J., Vaccarino, F.M., Sestan, N., and Rakic, P. (2007). Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc. Natl. Acad. Sci. USA 104, 20558–20563.10.1073/pnas.0710156104Search in Google Scholar PubMed PubMed Central

Brodaty, H., Seeher, K., and Gibson, L. (2012). Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int. Psychogeriatr. 24, 1034–1045.10.1017/S1041610211002924Search in Google Scholar PubMed

Brouillette, J. and Quirion, R. (2008). Transthyretin: a key gene involved in the maintenance of memory capacities during aging. Neurobiol. Aging 29, 1721–1732.10.1016/j.neurobiolaging.2007.04.007Search in Google Scholar PubMed

Burke, S.N. and Barnes, C.A. (2006). Neural plasticity in the ageing brain. Nat. Rev. Neurosci. 7, 30–40.10.1038/nrn1809Search in Google Scholar PubMed

Carpenter, W.T. and Koenig, J.I. (2008). The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33, 2061–2079.10.1038/sj.npp.1301639Search in Google Scholar PubMed PubMed Central

Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., and Torres-Aleman, I. (2002). Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat. Med. 8, 1390–1397.10.1038/nm1202-793Search in Google Scholar PubMed

Carro, E., Trejo, J.L., Spuch, C., Bohl, D., Heard, J.M., and Torres-Aleman, I. (2006). Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer’s-like neuropathology in rodents: new cues into the human disease? Neurobiol. Aging 27, 1618–1631.Search in Google Scholar

Castensson, A., Aberg, K., McCarthy, S., Saetre, P., Andersson, B., and Jazin, E. (2005). Serotonin receptor 2C (HTR2C) and schizophrenia: examination of possible medication and genetic influences on expression levels. Am. J. Med. Genet., Part B 134, 84–89.10.1002/ajmg.b.30151Search in Google Scholar PubMed

Castro-Alamancos, M.A. and Torres-Aleman, I. (1994). Learning of the conditioned eye-blink response is impaired by an antisense insulin-like growth factor I oligonucleotide. Proc. Natl. Acad. Sci. USA 91, 10203–10207.10.1073/pnas.91.21.10203Search in Google Scholar PubMed PubMed Central

Catts, V.S., Fung, S.J., Long, L.E., Joshi, D., Vercammen, A., Allen, K.M., Fillman, S.G., Rothmond, D.A., Sinclair, D., Tiwari, Y., et al. (2013). Rethinking schizophrenia in the context of normal neurodevelopment. Front. Cell. Neurosci. 7, 60.10.3389/fncel.2013.00060Search in Google Scholar PubMed PubMed Central

Chapman, C.D., Frey, W.H. 2nd, Craft, S., Danielyan, L., Hallschmid, M., Schioth, H.B., and Benedict, C. (2013). Intranasal treatment of central nervous system dysfunction in humans. Pharm. Res. 30, 2475–2484.10.1007/s11095-012-0915-1Search in Google Scholar PubMed PubMed Central

Chen, Q., Nakajima, A., Choi, S.H., Xiong, X., Sisodia, S.S., and Tang, Y.P. (2008). Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol. Dis. 29, 316–326.10.1016/j.nbd.2007.09.005Search in Google Scholar PubMed PubMed Central

Chen, D.Y., Stern, S.A., Garcia-Osta, A., Saunier-Rebori, B., Pollonini, G., Bambah-Mukku, D., Blitzer, R.D., and Alberini, C.M. (2011). A critical role for IGF-II in memory consolidation and enhancement. Nature 469, 491–497.10.1038/nature09667Search in Google Scholar PubMed PubMed Central

Chowdhury, S., Shepherd, J.D., Okuno, H., Lyford, G., Petralia, R.S., Plath, N., Kuhl, D., Huganir, R.L., and Worley, P.F. (2006). Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459.10.1016/j.neuron.2006.08.033Search in Google Scholar PubMed PubMed Central

Christoffel, D.J., Golden, S.A., Dumitriu, D., Robison, A.J., Janssen, W.G., Ahn, H.F., Krishnan, V., Reyes, C.M., Han, M.H., Ables, J.L., et al. (2011). IkappaB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314–321.10.1523/JNEUROSCI.4763-10.2011Search in Google Scholar PubMed PubMed Central

Clayton, E.L., Sue, N., Smillie, K.J., O’Leary, T., Bache, N., Cheung, G., Cole, A.R., Wyllie, D.J., Sutherland, C., Robinson, P.J., et al. (2010). Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles. Nat. Neurosci. 13, 845–851.10.1038/nn.2571Search in Google Scholar PubMed PubMed Central

Cohen, E. and Dillin, A. (2008). The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat. Rev. Neurosci. 9, 759–767.10.1038/nrn2474Search in Google Scholar PubMed PubMed Central

Cohen, E., Paulsson, J.F., Blinder, P., Burstyn-Cohen, T., Du, D., Estepa, G., Adame, A., Pham, H.M., Holzenberger, M., Kelly, J.W., et al. (2009). Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169.10.1016/j.cell.2009.11.014Search in Google Scholar PubMed PubMed Central

Cohen, E., Du, D., Joyce, D., Kapernick, E.A., Volovik, Y., Kelly, J.W., and Dillin, A. (2010). Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection. Aging Cell 9, 126–134.10.1111/j.1474-9726.2009.00541.xSearch in Google Scholar PubMed PubMed Central

Couillard-Despres, S., Winner, B., Karl, C., Lindemann, G., Schmid, P., Aigner, R., Laemke, J., Bogdahn, U., Winkler, J., Bischofberger, J., et al. (2006). Targeted transgene expression in neuronal precursors: watching young neurons in the old brain. Eur. J. Neurosci. 24, 1535–1545.10.1111/j.1460-9568.2006.05039.xSearch in Google Scholar PubMed

Davis, M., Myers, K.M., Chhatwal, J., and Ressler, K.J. (2006). Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx 3, 82–96.10.1016/j.nurx.2005.12.008Search in Google Scholar PubMed PubMed Central

Deng, W., Aimone, J.B., and Gage, F.H. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350.10.1038/nrn2822Search in Google Scholar PubMed PubMed Central

Denli, A.M., Tops, B.B., Plasterk, R.H., Ketting, R.F., and Hannon, G.J. (2004). Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231–235.10.1038/nature03049Search in Google Scholar PubMed

Duan, X., Chang, J.H., Ge, S., Faulkner, R.L., Kim, J.Y., Kitabatake, Y., Liu, X.B., Yang, C.H., Jordan, J.D., Ma, D.K., et al. (2007). Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130, 1146–1158.10.1016/j.cell.2007.07.010Search in Google Scholar PubMed PubMed Central

Dupret, D., Revest, J.M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., Abrous, D.N., and Piazza, P.V. (2008). Spatial relational memory requires hippocampal adult neurogenesis. PloS One 3, e1959.10.1371/journal.pone.0001959Search in Google Scholar PubMed PubMed Central

Earls, L.R., Fricke, R.G., Yu, J., Berry, R.B., Baldwin, L.T., and Zakharenko, S.S. (2012). Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J. Neurosci. 32, 14132–14144.10.1523/JNEUROSCI.1312-12.2012Search in Google Scholar PubMed PubMed Central

Elias, G.M., Funke, L., Stein, V., Grant, S.G., Bredt, D.S., and Nicoll, R.A. (2006). Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52, 307–320.10.1016/j.neuron.2006.09.012Search in Google Scholar PubMed

Encinas, J.M., Michurina, T.V., Peunova, N., Park, J.H., Tordo, J., Peterson, D.A., Fishell, G., Koulakov, A., and Enikolopov, G. (2011). Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579.10.1016/j.stem.2011.03.010Search in Google Scholar PubMed PubMed Central

Enwere, E., Shingo, T., Gregg, C., Fujikawa, H., Ohta, S., and Weiss, S. (2004). Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365.10.1523/JNEUROSCI.2751-04.2004Search in Google Scholar PubMed PubMed Central

Fenelon, K., Mukai, J., Xu, B., Hsu, P.K., Drew, L.J., Karayiorgou, M., Fischbach, G.D., Macdermott, A.B., and Gogos, J.A. (2011). Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc. Natl. Acad. Sci. USA 108, 4447–4452.10.1073/pnas.1101219108Search in Google Scholar PubMed PubMed Central

Fenelon, K., Xu, B., Lai, C.S., Mukai, J., Markx, S., Stark, K.L., Hsu, P.K., Gan, W.B., Fischbach, G.D., MacDermott, A.B., et al. (2013). The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J. Neurosci. 33, 14825–14839.10.1523/JNEUROSCI.1611-13.2013Search in Google Scholar PubMed PubMed Central

Fernandez, A.M. and Torres-Aleman, I. (2012). The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 13, 225–239.10.1038/nrn3209Search in Google Scholar PubMed

Fernandez, C., Tatard, V.M., Bertrand, N., and Dahmane, N. (2010). Differential modulation of Sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network. Dev. Neurosci. 32, 59–70.10.1159/000274458Search in Google Scholar PubMed PubMed Central

Fineberg, S.K., Kosik, K.S., and Davidson, B.L. (2009). MicroRNAs potentiate neural development. Neuron 64, 303–309.10.1016/j.neuron.2009.10.020Search in Google Scholar PubMed

Fleming, C.E., Nunes, A.F., and Sousa, M.M. (2009). Transthyretin: more than meets the eye. Prog. Neurobiol. 89, 266–276.10.1016/j.pneurobio.2009.07.007Search in Google Scholar PubMed

Forstner, A.J., Degenhardt, F., Schratt, G., and Nothen, M.M. (2013). MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review. Front. Mol. Neurosci. 6, 47.Search in Google Scholar

Francis, G.J., Martinez, J.A., Liu, W.Q., Xu, K., Ayer, A., Fine, J., Tuor, U.I., Glazner, G., Hanson, L.R., Frey, W.H. 2nd, et al. (2008). Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 131, 3311–3334.10.1093/brain/awn288Search in Google Scholar PubMed

Ghashghaei, H.T., Weber, J., Pevny, L., Schmid, R., Schwab, M.H., Lloyd, K.C., Eisenstat, D.D., Lai, C., and Anton, E.S. (2006). The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone. Proc. Natl. Acad. Sci. USA 103, 1930–1935.10.1073/pnas.0510410103Search in Google Scholar PubMed PubMed Central

Ghosh, P., Dahms, N.M., and Kornfeld, S. (2003). Mannose 6-phosphate receptors: new twists in the tale. Nat. Rev. Mol. Cell Biol. 4, 202–212.10.1038/nrm1050Search in Google Scholar PubMed

Goodman, A.B. (1998). Is transthyretin (TTR) disrupted by a trinucleotide repeat expansion in a schizophrenia kindred? Am. J. Med. Genet. 81, 347–348.Search in Google Scholar

Gothelf, D., Schneider, M., Green, T., Debbane, M., Frisch, A., Glaser, B., Zilkha, H., Schaer, M., Weizman, A., and Eliez, S. (2013). Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. J. Am. Acad. Child Adolesc. Psychiatry 52, 1192–1203 e1193.Search in Google Scholar

Green, T., Gothelf, D., Glaser, B., Debbane, M., Frisch, A., Kotler, M., Weizman, A., and Eliez, S. (2009). Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J. Am. Acad. Child Adolesc. Psychiatry 48, 1060–1068.10.1097/CHI.0b013e3181b76683Search in Google Scholar PubMed

Gregory, R.I., Yan, K.P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N., and Shiekhattar, R. (2004). The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240.10.1038/nature03120Search in Google Scholar PubMed

Guzowski, J.F., Lyford, G.L., Stevenson, G.D., Houston, F.P., McGaugh, J.L., Worley, P.F., and Barnes, C.A. (2000). Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001.10.1523/JNEUROSCI.20-11-03993.2000Search in Google Scholar

Harvey, P.D., Reichenberg, A., Bowie, C.R., Patterson, T.L., and Heaton, R.K. (2010). The course of neuropsychological performance and functional capacity in older patients with schizophrenia: influences of previous history of long-term institutional stay. Biol. Psychiatry 67, 933–939.10.1016/j.biopsych.2010.01.008Search in Google Scholar PubMed PubMed Central

Hawkes, C. and Kar, S. (2004). The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Res. Brain Res. Rev. 44, 117–140.10.1016/j.brainresrev.2003.11.002Search in Google Scholar PubMed

Herrmann, O., Baumann, B., de Lorenzi, R., Muhammad, S., Zhang, W., Kleesiek, J., Malfertheiner, M., Kohrmann, M., Potrovita, I., Maegele, I., et al. (2005). IKK mediates ischemia-induced neuronal death. Nat. Med. 11, 1322–1329.10.1038/nm1323Search in Google Scholar PubMed

Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., and Le Bouc, Y. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187.10.1038/nature01298Search in Google Scholar PubMed

Howard, M.A., Elias, G.M., Elias, L.A., Swat, W., and Nicoll, R.A. (2010). The role of SAP97 in synaptic glutamate receptor dynamics. Proc. Natl. Acad. Sci. USA 107, 3805–3810.10.1073/pnas.0914422107Search in Google Scholar PubMed PubMed Central

Huang, J.T., Leweke, F.M., Oxley, D., Wang, L., Harris, N., Koethe, D., Gerth, C.W., Nolden, B.M., Gross, S., Schreiber, D., et al. (2006). Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med. 3, e428.10.1371/journal.pmed.0030428Search in Google Scholar PubMed PubMed Central

Im, H.I. and Kenny, P.J. (2012). MicroRNAs in neuronal function and dysfunction. Trends Neurosci. 35, 325–334.10.1016/j.tins.2012.01.004Search in Google Scholar PubMed PubMed Central

Insel, T.R. (2010). Rethinking schizophrenia. Nature 468, 187–193.10.1038/nature09552Search in Google Scholar PubMed

Iwamoto, K., Bundo, M., and Kato, T. (2009). Serotonin receptor 2C and mental disorders: genetic, expression and RNA editing studies. RNA Biol. 6, 248–253.10.4161/rna.6.3.8370Search in Google Scholar PubMed

Jaaro-Peled, H., Hayashi-Takagi, A., Seshadri, S., Kamiya, A., Brandon, N.J., and Sawa, A. (2009). Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 32, 485–495.10.1016/j.tins.2009.05.007Search in Google Scholar PubMed PubMed Central

Kachiwala, S.J., Harris, S.E., Wright, A.F., Hayward, C., Starr, J.M., Whalley, L.J., and Deary, I.J. (2005). Genetic influences on oxidative stress and their association with normal cognitive ageing. Neurosci. Lett. 386, 116–120.10.1016/j.neulet.2005.05.067Search in Google Scholar PubMed

Kalus, I., Salmen, B., Viebahn, C., von Figura, K., Schmitz, D., D’Hooge, R., and Dierks, T. (2009). Differential involvement of the extracellular 6-O-endosulfatases Sulf1 and Sulf2 in brain development and neuronal and behavioural plasticity. J. Cell. Mol. Med. 13, 4505–4521.10.1111/j.1582-4934.2008.00558.xSearch in Google Scholar PubMed PubMed Central

Karayiorgou, M., Morris, M.A., Morrow, B., Shprintzen, R.J., Goldberg, R., Borrow, J., Gos, A., Nestadt, G., Wolyniec, P.S., Lasseter, V.K., et al. (1995). Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92, 7612–7616.10.1073/pnas.92.17.7612Search in Google Scholar PubMed PubMed Central

Karayiorgou, M., Simon, T.J., and Gogos, J.A. (2010). 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat. Rev. Neurosci. 11, 402–416.10.1038/nrn2841Search in Google Scholar PubMed PubMed Central

Karl, T. (2013). Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models. Front. Behav. Neurosci. 7, 106.10.3389/fnbeh.2013.00106Search in Google Scholar PubMed PubMed Central

Kempermann, G. (2003). Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130, 391–399.10.1242/dev.00203Search in Google Scholar PubMed

Kim, J.Y., Liu, C.Y., Zhang, F., Duan, X., Wen, Z., Song, J., Feighery, E., Lu, B., Rujescu, D., St Clair, D., et al. (2012). Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia. Cell 148, 1051–1064.10.1016/j.cell.2011.12.037Search in Google Scholar PubMed PubMed Central

Kitamura, T., Kahn, C.R., and Accili, D. (2003). Insulin receptor knockout mice. Annu. Rev. Physiol. 65, 313–332.10.1146/annurev.physiol.65.092101.142540Search in Google Scholar PubMed

Kitazawa, S. (2002). Neurobiology: ready to unlearn. Nature 416, 270–273.10.1038/416270aSearch in Google Scholar PubMed

Kornack, D.R. and Rakic, P. (1999). Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl. Acad. Sci. USA 96, 5768–5773.10.1073/pnas.96.10.5768Search in Google Scholar PubMed PubMed Central

Lazarov, O. and Marr, R.A. (2010). Neurogenesis and Alzheimer’s disease: at the crossroads. Exp. Neurol. 223, 267–281.10.1016/j.expneurol.2009.08.009Search in Google Scholar PubMed PubMed Central

Lazarov, O., Mattson, M.P., Peterson, D.A., Pimplikar, S.W., and van Praag, H. (2010). When neurogenesis encounters aging and disease. Trends Neurosci. 33, 569–579.10.1016/j.tins.2010.09.003Search in Google Scholar PubMed PubMed Central

Lehtinen, M.K., Zappaterra, M.W., Chen, X., Yang, Y.J., Hill, A.D., Lun, M., Maynard, T., Gonzalez, D., Kim, S., Ye, P., et al. (2011). The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893–905.10.1016/j.neuron.2011.01.023Search in Google Scholar

Leuner, B., Kozorovitskiy, Y., Gross, C.G., and Gould, E. (2007). Diminished adult neurogenesis in the marmoset brain precedes old age. Proc. Natl. Acad. Sci. USA 104, 17169–17173.10.1073/pnas.0708228104Search in Google Scholar

Lie, D.C., Colamarino, S.A., Song, H.J., Desire, L., Mira, H., Consiglio, A., Lein, E.S., Jessberger, S., Lansford, H., Dearie, A.R., et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375.10.1038/nature04108Search in Google Scholar

Lugert, S., Basak, O., Knuckles, P., Haussler, U., Fabel, K., Gotz, M., Haas, C.A., Kempermann, G., Taylor, V., and Giachino, C. (2010). Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6, 445–456.10.1016/j.stem.2010.03.017Search in Google Scholar

Mahar, I., Tan, S., Davoli, M.A., Dominguez-Lopez, S., Qiang, C., Rachalski, A., Turecki, G., and Mechawar, N. (2011). Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PloS One 6, e26610.10.1371/journal.pone.0026610Search in Google Scholar

Mao, Y., Ge, X., Frank, C.L., Madison, J.M., Koehler, A.N., Doud, M.K., Tassa, C., Berry, E.M., Soda, T., Singh, K.K., et al. (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136, 1017–1031.10.1016/j.cell.2008.12.044Search in Google Scholar

Margolis, B. and Borg, J.P. (2005). Apicobasal polarity complexes. J. Cell Sci. 118, 5157–5159.10.1242/jcs.02597Search in Google Scholar

Masellis, M., Basile, V., Meltzer, H.Y., Lieberman, J.A., Sevy, S., Macciardi, F.M., Cola, P., Howard, A., Badri, F., Nothen, M.M., et al. (1998). Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 19, 123–132.10.1016/S0893-133X(98)00007-4Search in Google Scholar

Meffert, M.K., Chang, J.M., Wiltgen, B.J., Fanselow, M.S., and Baltimore, D. (2003). NF-kappa B functions in synaptic signaling and behavior. Nat. Neurosci. 6, 1072–1078.10.1038/nn1110Search in Google Scholar PubMed

Messier, C. and Teutenberg, K. (2005). The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer’s disease. Neural Plast. 12, 311–328.10.1155/NP.2005.311Search in Google Scholar PubMed PubMed Central

Millar, J.K., Wilson-Annan, J.C., Anderson, S., Christie, S., Taylor, M.S., Semple, C.A., Devon, R.S., St Clair, D.M., Muir, W.J., Blackwood, D.H., et al. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423.10.1093/hmg/9.9.1415Search in Google Scholar

Mira, H., Andreu, Z., Suh, H., Lie, D.C., Jessberger, S., Consiglio, A., San Emeterio, J., Hortiguela, R., Marques-Torrejon, M.A., Nakashima, K., et al. (2010). Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell 7, 78–89.10.1016/j.stem.2010.04.016Search in Google Scholar

Murphy, K.C., Jones, L.A., and Owen, M.J. (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56, 940–945.10.1001/archpsyc.56.10.940Search in Google Scholar

Myers, K.M. and Davis, M. (2002). Behavioral and neural analysis of extinction. Neuron 36, 567–584.10.1016/S0896-6273(02)01064-4Search in Google Scholar

Nagai, T., Yamada, K., Kim, H.C., Kim, Y.S., Noda, Y., Imura, A., Nabeshima, Y., and Nabeshima, T. (2003). Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J. 17, 50–52.10.1096/fj.02-0448fjeSearch in Google Scholar PubMed

Narayan, S., Tang, B., Head, S.R., Gilmartin, T.J., Sutcliffe, J.G., Dean, B., and Thomas, E.A. (2008). Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res. 1239, 235–248.10.1016/j.brainres.2008.08.023Search in Google Scholar PubMed PubMed Central

Olariu, A., Cleaver, K.M., and Cameron, H.A. (2007). Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle. J. Comp. Neurol. 501, 659–667.10.1002/cne.21268Search in Google Scholar PubMed

Olde Loohuis, N.F., Kos, A., Martens, G.J., Van Bokhoven, H., Nadif Kasri, N., and Aschrafi, A. (2012). MicroRNA networks direct neuronal development and plasticity. Cell Mol. Life Sci. 69, 89–102.10.1007/s00018-011-0788-1Search in Google Scholar PubMed PubMed Central

Ouchi, Y., Banno, Y., Shimizu, Y., Ando, S., Hasegawa, H., Adachi, K., and Iwamoto, T. (2013). Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11.2 deletion-associated schizophrenia can be rescued by IGF2. J. Neurosci. 33, 9408–9419.10.1523/JNEUROSCI.2700-12.2013Search in Google Scholar PubMed PubMed Central

Pandini, G., Medico, E., Conte, E., Sciacca, L., Vigneri, R., and Belfiore, A. (2003). Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. J. Biol. Chem. 278, 42178–42189.10.1074/jbc.M304980200Search in Google Scholar PubMed

Parsons, R.G. and Ressler, K.J. (2013). Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146–153.10.1038/nn.3296Search in Google Scholar

Pennartz, S., Belvindrah, R., Tomiuk, S., Zimmer, C., Hofmann, K., Conradt, M., Bosio, A., and Cremer, H. (2004). Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis. Mol. Cell. Neurosci. 25, 692–706.10.1016/j.mcn.2003.12.011Search in Google Scholar

Puech, A., Saint-Jore, B., Funke, B., Gilbert, D.J., Sirotkin, H., Copeland, N.G., Jenkins, N.A., Kucherlapati, R., Morrow, B., and Skoultchi, A.I. (1997). Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc. Natl. Acad. Sci. USA 94, 14608–14613.10.1073/pnas.94.26.14608Search in Google Scholar

Reif, A., Fritzen, S., Finger, M., Strobel, A., Lauer, M., Schmitt, A., and Lesch, K.P. (2006). Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 11, 514–522.10.1038/ in Google Scholar

Reif, A., Schmitt, A., Fritzen, S., and Lesch, K.P. (2007). Neurogenesis and schizophrenia: dividing neurons in a divided mind? Eur. Arch. Psychiatry Clin. Neurosci. 257, 290–299.10.1007/s00406-007-0733-3Search in Google Scholar

Remacle-Bonnet, M., Garrouste, F., Baillat, G., Andre, F., Marvaldi, J., and Pommier, G. (2005). Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily. Am. J. Pathol. 167, 761–773.10.1016/S0002-9440(10)62049-4Search in Google Scholar

Renner, D.B., Svitak, A.L., Gallus, N.J., Ericson, M.E., Frey, W.H. 2nd, and Hanson, L.R. (2012). Intranasal delivery of insulin via the olfactory nerve pathway. J. Pharm. Pharmacol. 64, 1709–1714.10.1111/j.2042-7158.2012.01555.xSearch in Google Scholar PubMed

Ross, C.A. and Margolis, R.L. (2009). Schizophrenia: a point of disruption. Nature 458, 976–977.10.1038/458976aSearch in Google Scholar PubMed

Ross, C.A., Margolis, R.L., Reading, S.A., Pletnikov, M., and Coyle, J.T. (2006). Neurobiology of schizophrenia. Neuron 52, 139–153.10.1016/j.neuron.2006.09.015Search in Google Scholar PubMed

Russo, V.C., Gluckman, P.D., Feldman, E.L., and Werther, G.A. (2005). The insulin-like growth factor system and its pleiotropic functions in brain. Endocrine Rev. 26, 916–943.10.1210/er.2004-0024Search in Google Scholar PubMed

Sacco, A., Morcavallo, A., Pandini, G., Vigneri, R., and Belfiore, A. (2009). Differential signaling activation by insulin and insulin-like growth factors I and II upon binding to insulin receptor isoform A. Endocrinology 150, 3594–3602.10.1210/en.2009-0377Search in Google Scholar PubMed

Sawallisch, C., Berhorster, K., Disanza, A., Mantoani, S., Kintscher, M., Stoenica, L., Dityatev, A., Sieber, S., Kindler, S., Morellini, F., et al. (2009). The insulin receptor substrate of 53 kDa (IRSp53) limits hippocampal synaptic plasticity. J. Biol. Chem. 284, 9225–9236.10.1074/jbc.M808425200Search in Google Scholar PubMed PubMed Central

Scheidereit, C. (2006). IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 25, 6685–6705.10.1038/sj.onc.1209934Search in Google Scholar PubMed

Schmeisser, M.J., Baumann, B., Johannsen, S., Vindedal, G.F., Jensen, V., Hvalby, O.C., Sprengel, R., Seither, J., Maqbool, A., Magnutzki, A., et al. (2012). IkappaB kinase/nuclear factor kappaB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. J. Neurosci. 32, 5688–5703.10.1523/JNEUROSCI.0111-12.2012Search in Google Scholar PubMed PubMed Central

Scolnick, J.A., Cui, K., Duggan, C.D., Xuan, S., Yuan, X.B., Efstratiadis, A., and Ngai, J. (2008). Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57, 847–857.10.1016/j.neuron.2008.01.027Search in Google Scholar PubMed PubMed Central

Semba, R.D., Moghekar, A.R., Hu, J., Sun, K., Turner, R., Ferrucci, L., and O’Brien, R. (2014). Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci. Lett. 558, 37–40.10.1016/j.neulet.2013.10.058Search in Google Scholar PubMed PubMed Central

Shemesh, E., Rudich, A., Harman-Boehm, I., and Cukierman-Yaffe, T. (2012). Effect of intranasal insulin on cognitive function: a systematic review. J. Clin. Endocrinol. Metab. 97, 366–376.10.1210/jc.2011-1802Search in Google Scholar PubMed

Shiozaki, M., Yoshimura, K., Shibata, M., Koike, M., Matsuura, N., Uchiyama, Y., and Gotow, T. (2008). Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. Neuroscience 152, 924–941.10.1016/j.neuroscience.2008.01.032Search in Google Scholar PubMed

Simon, T.J., Takarae, Y., DeBoer, T., McDonald-McGinn, D.M., Zackai, E.H., and Ross, J.L. (2008). Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes. Neuropsychologia 46, 82–94.10.1016/j.neuropsychologia.2007.08.016Search in Google Scholar PubMed PubMed Central

Skeberdis, V.A., Lan, J., Zheng, X., Zukin, R.S., and Bennett, M.V. (2001). Insulin promotes rapid delivery of N-methyl-D-aspartate receptors to the cell surface by exocytosis. Proc. Natl. Acad. Sci. USA 98, 3561–3566.10.1073/pnas.051634698Search in Google Scholar PubMed PubMed Central

Stark, K.L., Xu, B., Bagchi, A., Lai, W.S., Liu, H., Hsu, R., Wan, X., Pavlidis, P., Mills, A.A., Karayiorgou, M., et al. (2008). Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40, 751–760.10.1038/ng.138Search in Google Scholar PubMed

Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., et al. (2008). Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236.10.1038/nature07229Search in Google Scholar PubMed PubMed Central

Stone, W.S. and Hsi, X. (2011). Declarative memory deficits and schizophrenia: problems and prospects. Neurobiol. Learn. Mem. 96, 544–552.10.1016/j.nlm.2011.04.006Search in Google Scholar PubMed

Suh, H., Consiglio, A., Ray, J., Sawai, T., D’Amour, K.A., and Gage, F.H. (2007). In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell 1, 515–528.10.1016/j.stem.2007.09.002Search in Google Scholar PubMed PubMed Central

Taubenfeld, S.M., Milekic, M.H., Monti, B., and Alberini, C.M. (2001). The consolidation of new but not reactivated memory requires hippocampal C/EBPbeta. Nat. Neurosci. 4, 813–818.10.1038/90520Search in Google Scholar PubMed

Thorne, R.G., Pronk, G.J., Padmanabhan, V., and Frey, W.H. 2nd. (2004). Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127, 481–496.10.1016/j.neuroscience.2004.05.029Search in Google Scholar PubMed

van der Heide, L.P., Ramakers, G.M., and Smidt, M.P. (2006). Insulin signaling in the central nervous system: learning to survive. Prog. Neurobiol. 79, 205–221.10.1016/j.pneurobio.2006.06.003Search in Google Scholar PubMed

van Praag, H., Schinder, A.F., Christie, B.R., Toni, N., Palmer, T.D., and Gage, F.H. (2002). Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034.10.1038/4151030aSearch in Google Scholar PubMed

van Praag, H., Shubert, T., Zhao, C., and Gage, F.H. (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685.10.1523/JNEUROSCI.1731-05.2005Search in Google Scholar PubMed PubMed Central

Wan, Q., Xiong, Z.G., Man, H.Y., Ackerley, C.A., Braunton, J., Lu, W.Y., Becker, L.E., MacDonald, J.F., and Wang, Y.T. (1997). Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388, 686–690.10.1038/41792Search in Google Scholar PubMed

Wiescholleck, V. and Manahan-Vaughan, D. (2013). Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis. Neuropharmacology 74, 48–58.10.1016/j.neuropharm.2013.01.001Search in Google Scholar PubMed

Wilson, R.S., Arnold, S.E., Schneider, J.A., Tang, Y., and Bennett, D.A. (2007). The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J. Neurol. Neurosurg. Psychiatry 78, 30–35.10.1136/jnnp.2006.099721Search in Google Scholar PubMed PubMed Central

Winner, B., Kohl, Z., and Gage, F.H. (2011). Neurodegenerative disease and adult neurogenesis. Eur. J. Neurosci. 33, 1139–1151.10.1111/j.1460-9568.2011.07613.xSearch in Google Scholar PubMed

Wright, C., Turner, J.A., Calhoun, V.D., and Perrone-Bizzozero, N. (2013). Potential impact of miR-137 and its targets in schizophrenia. Front. Genet. 4, 58.10.3389/fgene.2013.00058Search in Google Scholar PubMed PubMed Central

Xu, B., Roos, J.L., Levy, S., van Rensburg, E.J., Gogos, J.A., and Karayiorgou, M. (2008). Strong association of de novo copy number mutations with sporadic schizophrenia. Nat. Genet. 40, 880–885.10.1038/ng.162Search in Google Scholar PubMed

Xu, B., Hsu, P.K., Stark, K.L., Karayiorgou, M., and Gogos, J.A. (2013). Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 152, 262–275.10.1016/j.cell.2012.11.052Search in Google Scholar PubMed PubMed Central

Yu, R.K., Suzuki, Y., and Yanagisawa, M. (2010). Membrane glycolipids in stem cells. FEBS Lett. 584, 1694–1699.10.1016/j.febslet.2009.08.026Search in Google Scholar PubMed PubMed Central

Zhao, C., Deng, W., and Gage, F.H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660.10.1016/j.cell.2008.01.033Search in Google Scholar PubMed

Ziegler, A.N., Schneider, J.S., Qin, M., Tyler, W.A., Pintar, J.E., Fraidenraich, D., Wood, T.L., and Levison, S.W. (2012). IGF-II promotes stemness of neural restricted precursors. Stem Cells 30, 1265–1276.10.1002/stem.1095Search in Google Scholar PubMed PubMed Central

Received: 2014-2-11
Accepted: 2014-3-28
Published Online: 2014-4-26
Published in Print: 2014-8-1

© 2014 by De Gruyter