These two recent exciting studies demonstrate that local inflammation inhibits adult neurogenesis in the hippocampus in different diseased animal models [1,2]. The suppression of hippocampal neurogenesis by activated microglia may explain the cognitive dysfunction and adds another angle to the rationale behind immunotherapeutics in Alzheimer's disease. The authors showed that decreased neurogenesis was accompanied with, and probably fueled by, activation of microglia, as neurogenesis was tightly correlated to the degree of microglial activation. Further support comes from the use of nonsteroidal antiinflammatory drugs, like indomethacin, and a selective inhibitor of microglia activation, minocycline, which were able to restore hippocampal neurogenesis in inflammation without affecting neurogenesis in control animals [1].

Inflammatory changes—including microgliosis, astrocytosis, complement activation, cytokine elevation, and acute phase protein changes—are thought to represent, at least in part, a response to the early accumulation of Aβ1-42 in the AD brain...  Read more

These two recent exciting studies demonstrate that local inflammation inhibits adult neurogenesis in the hippocampus in different diseased animal models [1,2]. The suppression of hippocampal neurogenesis by activated microglia may explain the cognitive dysfunction and adds another angle to the rationale behind immunotherapeutics in Alzheimer's disease. The authors showed that decreased neurogenesis was accompanied with, and probably fueled by, activation of microglia, as neurogenesis was tightly correlated to the degree of microglial activation. Further support comes from the use of nonsteroidal antiinflammatory drugs, like indomethacin, and a selective inhibitor of microglia activation, minocycline, which were able to restore hippocampal neurogenesis in inflammation without affecting neurogenesis in control animals [1].

Inflammatory changes—including microgliosis, astrocytosis, complement activation, cytokine elevation, and acute phase protein changes—are thought to represent, at least in part, a response to the early accumulation of Aβ1-42 in the AD brain [3-6]. It appears that Aβ or its fibrillated form is recognized in the CNS as a molecule that needs to be cleared and provokes activation of microglia and astrocytes.

Immunotherapy aimed at Aβ vaccination in AD transgenic mice raised unprecedented hopes for an effective treatment of AD. On the efficacy side, there is clear evidence that Aβ immunization in mice induces a clearance of Aβ plaques and improves associated cognitive disturbances [7-13]. It appears that the induction of antibodies to Aβ plays the primary role in the vaccine-mediated clearance of Aβ from the brain, as passive transfer of Aβ antibodies has shown similar beneficial neuropathological effects [13].

The recent clinical trials of AD immunotherapy failed because of unexpected neuroinflammation, and a major concern may be attributed to potential proinflammatory consequences following Aβ immunization, which may lead to overactivation of microglia, even leading to acceleration of neurodegeneration.

Brain inflammation causes inhibition of neurogenesis both in the basal continuous formation of new neurons in the intact hippocampal formation and in the increased neurogenesis in response to a brain insult. The impairment of neurogenesis depends on the degree of microglia activation, irrespective of whether there is damage or not in the surrounding tissue. While neurogenesis appears to be increased in the brains of patients with AD, progressive cell loss is still observed [14,15]. This may be due to the disruptive micro environment to neurogenesis in the AD brain which may be toxic to new neurons [15].

The beneficial effect of immunotherapy on Aβ clearance could be exploited, avoiding inflammation by controlling microglial activation and supporting neurogenesis. This could be prominent amongst those factors that determine whether immune therapy will be successful as a treatment for AD patients [16].

Plaque clearance as a result of immunotherapy may depend on multiple mechanisms, one involving direct interaction of antibodies, or F(ab')2 fragments, with the deposits resulting in disaggregation, and another involving cell-mediated clearance, possibly involving Fc receptor activation. The two mechanisms may occur independently, or may operate in tandem, with cellular removal of amyloid-β after disaggregation [17].

However, Fc regions of antibody-antigen complexes, amplified by cellular mediators and activated complement, via Fc receptors (FcR), may initiate the inflammatory response [18].

No data are available so far on the quantitative decrease of Aβ concentration necessary to reduce Aβ deposition and the amount of antibodies required for efficient immunotherapy which might at the same time avoid additional inflammation.

Modulation of the FcR pathway may be an efficient practical therapeutic approach for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD. One of these is the administration of intravenous immunoglobulin (IVIg), which has well-recognized antiinflammatory activities independent of the antigen-specific effect [19].

Another approach may be passive immunization with antibodies devoid of Fc, which may prevent overactivation of microglia and, thus, attenuation of autoantibody-triggered neuroinflammation. The ability of single-chain antibody 508F(Fv) to dissolve already formed Aβ fibrils suggests that only the antigen-binding site of the antibodies (Fab) was involved in modulation of β amyloid conformation and not the Fc region [20]. Studies with F(ab')2 fragments of anti-Aβ antibodies using in-vivo topical application demonstrated that the mechanism does not require Fc receptor-mediated cellular activation in plaque clearance by immunotherapy [21].

To definitively ascertain the role of microglial FcR in Aβ immunotherapies, APP Tg2576 mice bred into FcR-/- mice were used [22]. Data show that microglia isolated from FcR γ-/- mice exhibit almost no uptake of anti-Aβ immune complexes via FcR. Aggregated Aβ was readily scavenged by both FcR-γ+/+ and FcR-γ-/- microglia in the absence of anti-Aβ. Thus, there did not appear to be any defects in the non-FcR-mediated Aβ uptake by microglia in the FcR-γ-/- mice [22].

Fc receptors also interact bidirectionally with complement receptor proteins [23-27]. Complement activation in AD brain has been proposed to be especially crucial to the phenomenon of "bystander lysis," in which healthy neuronal tissue adjacent to plaques is thought to undergo nonspecific injury and degeneration [28,29].

Proinflammatory cytokines may be involved in the interaction of Fc receptors and complement biosynthesis, as IL-6, shown to modulate production of both C3 and C9 complement proteins following immune stimulation [18,23-25]. C9 is an integral member of membrane attack complex, which is the mechanism for complement-mediated cell lysis, raising the possibility that activation of Fc receptors may very well clear Aβ, but might drastically increase local inflammation and neuronal injury in the vicinity of Aβ plaques in the process [3]. Furthermore, in a recent paper, Kemermann and Neumann [26] claim that IL-6 is interfering with the production of new neurons, since it diverts neuronal progenitor cells to become astrocytes rather than neurons.

It is believed that the discovery that the diseased adult human brain is capable of neurogenesis in response to neuronal loss will be of major relevance for development of therapeutic approaches in the treatment of neurodegenerative diseases.

It is tempting to believe that the beneficial effect of the immunotherapy might stem less from alleviation of the toxic agent and more so from promotion and/or restoration of neurogenesis, all resulting in a normal number of functioning neurons.

References:
1. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 100(23):13632-7. Abstract

2. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 302(5651):1760-5. Abstract

3. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F et al. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999 286: 2352 2355. Abstract

4. Cooper NR, Kalaria RN, McGeer P L and Rogers J. Key issues in Alzheimer's disease inflammation. Neurobiol Aging 2000 21: 451-453. Abstract

5. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer's disease. Neurobiol Aging 2000 21: 383-421. Abstract

6. Bradt BM, Kolb WP and Cooper NR. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med 1998 188: 431-438. Abstract

7. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K,Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G,Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8; 400(6740): 173-7. Abstract

8. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28; 408(6815): 982-5. Erratum in: Nature 2001 Aug 9;412(6847):660. Abstract

9. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28; 408(6815): 979-82. Abstract

10. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. 2000 Oct; 48(4): 567-79. Abstract

11. Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Desai R, Hancock WW, Weiner HL, Selkoe DJ Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci. 2000; 920: 328-31. No abstract available. Abstract

12. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May; 5(5): 452-7. Abstract

13. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000 Aug; 6(8): 916-9. Abstract

14. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6; 101(1): 343-7. Epub 2003 Dec 05. Abstract

15. Rapoport M, Dawson HN, Binder LI, Vitek MP and Ferreira A Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30; 99(9): 6364-9. Epub 2002 Apr 16. Abstract

16. Solomon B. Immunological approaches as therapy for Alzheimer's disease. Expert Opin Biol Ther. 2002 Dec; 2(8): 907-17. Review. Abstract

17. Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman BT. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med. 2001 Mar; 7(3): 369-72. No abstract available. Abstract

18. Trotta R, Kanakaraj P, Perussia B. Fc gamma R-dependent mitogen-activated protein kinase activation in leukocytes: a common signal transduction event necessary for expression of TNF-alpha and early activation genes. J Exp Med. 1996 Sep 1; 184(3): 1027-35. Abstract

19. Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. Neurology. 2002 Dec 24; 59(12 Suppl 6): S13-21. Review. Abstract

20. Frenkel D, Solomon B and Benhar I. Modulation of Alzheimer's beta-amyloid neurotoxicity by site-directed single-chain antibody. J Neuroimmunol. 2000 Jul 1; 106(1-2): 23-31. Abstract

21. Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002 Sep 15; 22(18): 7873-8. Abstract

22. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci. 2003 Sep 17; 23(24): 8532-8. Abstract

23. Emmerling MR, M.D. Watson, C.A. Raby and K. Spiegel. The role of complement in Alzheimer's disease pathology. Biochim Biophys Acta. 2000 Jul 26; 1502(1): 158-71. Review. Abstract

24. Morikawa M, Harada N, Nunomura Y, Koike T, Hashimoto S, Soma G, Yoshida T. Fc gamma receptor-mediated biological activities of human leukemic cell lines and their modulation by transforming growth factor-beta 1 and interleukin 6. Cytokine. 1993 May; 5(3): 255-63. Abstract

25. Klegeris A, Schwab C, Bissonnette CJ and McGeer PL. Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders. Exp Gerontol. 2001 Jul; 36(7): 1179-88. Abstract

26. Kempermann G, Neumann H. Neuroscience. Microglia: the enemy within? Science. 2003 Dec 5; 302(5651): 1689-90. No abstract available. Abstract

View all comments by Beka Solomon

The discoveries that neurons that mediate birdsong in canaries are replaced by new neurons produced from stem cells, and that this turnover of the neurons is regulated by testosterone in a seasonal manner, have provided important insight into the control of neurogenesis by environmental factors. In their new study, Alvarez-Borda et al. provide evidence that BDNF promotes the survival of newly generated neurons in the high vocal center of the canaries. Remarkably, there is only a very tight time window of approximately two weeks following neurogenesis in the spring when BDNF is capable of promoting the long-term survival of the newly generated neurons. These findings have important implications for the regulation of adult neurogenesis in mammals as well as for the importance of neurogenesis in learning and memory processes.

Recent studies of neurogenesis in the hippocampus and forebrain of mice suggest that the continued production of new neurons is required for at least some aspects of learning and memory [1,2]. Presumably, newly generated neurons must integrate into neuronal...  Read more

The discoveries that neurons that mediate birdsong in canaries are replaced by new neurons produced from stem cells, and that this turnover of the neurons is regulated by testosterone in a seasonal manner, have provided important insight into the control of neurogenesis by environmental factors. In their new study, Alvarez-Borda et al. provide evidence that BDNF promotes the survival of newly generated neurons in the high vocal center of the canaries. Remarkably, there is only a very tight time window of approximately two weeks following neurogenesis in the spring when BDNF is capable of promoting the long-term survival of the newly generated neurons. These findings have important implications for the regulation of adult neurogenesis in mammals as well as for the importance of neurogenesis in learning and memory processes.

Recent studies of neurogenesis in the hippocampus and forebrain of mice suggest that the continued production of new neurons is required for at least some aspects of learning and memory [1,2]. Presumably, newly generated neurons must integrate into neuronal circuits in order to function in learning and memory, and this requires that they migrate to the appropriate site, differentiate into the relevant phenotype, and form functional synapses. Of course, functional neurogenesis also requires that the neurons survive, which in many instances is not the case, as indeed many newly generated neurons undergo apoptosis. As in the canary, it has been shown that BDNF promotes the differentiation [3] and survival [4] of newly generated neurons in the mammalian brain.

Might there be a role for altered neurogenesis in the cognitive dysfunction that occurs in Alzheimer's disease [AD]? Neurogenesis is decreased during aging [5], and aging is a major risk factor for AD. Studies of transgenic mice with amyloid deposits in their brains, and of cultured human neural stem cells exposed to amyloid-β peptide, suggest that increased levels of Aβ can impair neurogenesis [6]. However, analyses of brain tissue from AD patients suggested that neurogenesis is not reduced and even might be increased in AD [7]. It therefore remains to be determined whether impairment of neurogenesis contributes to cognitive dysfunction in mouse models or AD patients. Nevertheless, levels of BDNF, [8] and its high affinity receptor TrkB [9], are decreased in affected brain regions in AD patients, and there are indications that polymorphisms in the BDNF gene can affect the risk of AD [10]. A deficit in BDNF signaling would be expected to impair synaptic plasticity and might also suppress neurogenesis in AD.

References:
1. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12[5]:578-84. Abstract

2. Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001 Dec 6;32[5]:911-26. Erratum in: Neuron 2002 Jan 17;33[2]:313. Abstract

3. Cheng A, Wang S, Cai J, Rao MS, Mattson MP. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol. 2003 Jun 15;258[2]:319-33. Abstract

4. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002 Sep;82[6]:1367-75. Abstract

Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996 Mar 15;16[6]:2027-33. Abstract

6. Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83[6]:1509-24. Abstract

7. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101[1]:343-7. Abstract

8. Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res Mol Brain Res. 1997 Oct 3;49[1-2]:71-81. Abstract

9. Allen SJ, Wilcock GK, Dawbarn D. Profound and selective loss of catalytic TrkB immunoreactivity in Alzheimer's disease. Biochem Biophys Res Commun. 1999 Nov 2;264[3]:648-51. Abstract

10. Kunugi H, Ueki A, Otsuka M, Isse K, Hirasawa H, Kato N, Nabika T, Kobayashi S, Nanko S. A novel polymorphism of the brain-derived neurotrophic factor [BDNF] gene associated with late-onset Alzheimer's disease. Mol Psychiatry. 2001 Jan;6[1]:83-6. Abstract

View all comments by Mark Mattson

This report by Deisseroth and colleagues, that excitatory transmission stimulates neurogenesis in the hippocampus of rats, could have important implications for the pathogenesis and treatment of Alzheimer’s disease (AD).

In AD, as in several other neurological disorders, neurogenesis is increased (2), although the reason for this increase is unknown. Possible causes include the loss of an anti-proliferative effect that is normally imposed by intact tissue, or enhancement of neurogenesis by one or more proliferative factors released from damaged tissue. In either case, neurogenesis might represent an endogenous mechanism directed at repairing brain injury through cell replacement.

As Deisseroth and colleagues note, the bulk of prior evidence has suggested that excitatory amino acids inhibit neurogenesis, based largely on the neurogenesis-promoting effects of glutamate receptor antagonists (3). This would be consistent with a release-of-inhibition mechanism for injury-induced neurogenesis, in which neurogenesis is triggered by interruption of excitatory inputs that project...  Read more

This report by Deisseroth and colleagues, that excitatory transmission stimulates neurogenesis in the hippocampus of rats, could have important implications for the pathogenesis and treatment of Alzheimer’s disease (AD).

In AD, as in several other neurological disorders, neurogenesis is increased (2), although the reason for this increase is unknown. Possible causes include the loss of an anti-proliferative effect that is normally imposed by intact tissue, or enhancement of neurogenesis by one or more proliferative factors released from damaged tissue. In either case, neurogenesis might represent an endogenous mechanism directed at repairing brain injury through cell replacement.

As Deisseroth and colleagues note, the bulk of prior evidence has suggested that excitatory amino acids inhibit neurogenesis, based largely on the neurogenesis-promoting effects of glutamate receptor antagonists (3). This would be consistent with a release-of-inhibition mechanism for injury-induced neurogenesis, in which neurogenesis is triggered by interruption of excitatory inputs that project to neuroproliferative zones of the brain. However, to the extent that excitatory transmission enhances neurogenesis, injury-induced neurogenesis could result instead from excessive excitation, which has been implicated in the pathogenesis of a variety of cerebral disorders, including AD.

The therapeutic implications of the finding by Deisseroth and colleagues are most evident in the case of memantine, an NMDA-type glutamate receptor antagonist used in the treatment of moderate to severe AD (4). The beneficial effect of memantine in AD is widely ascribed to its anti-excitotoxic, neuroprotective action. However, if excitatory transmission activates neurogenesis, and if neurogenesis helps to preserve brain function in AD (which remains to be proven), drugs like memantine could adversely affect this adaptive response. [Editor’s note: see ARF Live Discussion on memantine.]

It is unlikely that we have heard the last on this subject. The apparent discrepancy between the neurogenesis-promoting effects of excitatory transmission and of excitatory amino acid antagonists may simply reflect the brain’s complexity and our limited understanding of how neuronal precursor cells are regulated. Systemically administered drugs act at a variety of sites in the brain, making their ultimate, integrated effects unpredictable. More work is needed to establish whether neurogenesis is a significant factor in brain repair and, if so, how it can best be optimized.

References:
1. Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC (2004) Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42:535-552. Abstract

2. Jin K, Peel A, Mao XO, Xie L, Cottrell B, Greenberg DA (2004) Increased hippocampal neurogenesis in brains of patients with Alzheimer's disease. Proc Natl Acad Sci USA 101:343-347. Abstract

3. Bernabeu R, Sharp FR (2000) NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab 20:1669-1680. Abstract

4. Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol Sep;2(9):539-47. Abstract

View all comments by David Greenberg

This is a very exciting study with clever designs and elegant executions. It addresses one of the most fundamental issues in the field of neurogenesis. Adult neurogenesis, occurring in the dentate gyrus of the hippocampus and olfactory bulb in the adult brains, is evolutionarily preserved in mammalian species, including rodents to monkeys to humans. The functional significance of adult dentate neurogenesis is not clear. One leading idea is that neurogenesis is needed for clearance of outdated memories [1]. It has been observed that the forebrain-specific knockout of presenilin-1, a gene whose mutations are responsible for a vast majority of cases of early-onset Alzheimer’s disease, resulted in a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus [1]. Behavioral experiments suggested that adult neurogenesis in the dentate gyrus may play a role in the clearance or destabilization of outdated hippocampal memory traces after cortical memory consolidation, thereby preventing the hippocampus from overload. This leads to the hypothesis that adult neurogenesis...  Read more

This is a very exciting study with clever designs and elegant executions. It addresses one of the most fundamental issues in the field of neurogenesis. Adult neurogenesis, occurring in the dentate gyrus of the hippocampus and olfactory bulb in the adult brains, is evolutionarily preserved in mammalian species, including rodents to monkeys to humans. The functional significance of adult dentate neurogenesis is not clear. One leading idea is that neurogenesis is needed for clearance of outdated memories [1]. It has been observed that the forebrain-specific knockout of presenilin-1, a gene whose mutations are responsible for a vast majority of cases of early-onset Alzheimer’s disease, resulted in a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus [1]. Behavioral experiments suggested that adult neurogenesis in the dentate gyrus may play a role in the clearance or destabilization of outdated hippocampal memory traces after cortical memory consolidation, thereby preventing the hippocampus from overload. This leads to the hypothesis that adult neurogenesis in the hippocampus is crucial for memory clearance of outdated memory [2, 3]. It is possible that impaired neurogenesis could be a contributing factor leading to an impairment of memory consolidation in Alzheimer’s patients during the early stage of the disease process. Deisseroth’s et al’s analysis of the coupling between excitation and neurogenesis is very interesting. It provides a potential mechanism for explaining how enrichment and running would lead to increased neurogenesis in the dentate gyrus. Their further investigation of the role of neurogenesis using computation modeling provides an insightful mechanism supporting the original experimental observation. It shows that such addition and removal of adult-born neurons in the upstream location of the hippocampal circuitry make it ideal to amplify the "destabilization" effect within the entire hippocampus, thus altering the attractor states corresponding to memories previously stored in the network. I personally think that this computational approach brings a fresh air to the field of neurogenesis!

References:
1. Feng, R., Rampon, C. Tang, Y., Shrom. D., Jin, J., Kyin, M., Sopher, B., Martin, GM., Kim, SH., Langdon, R.B., Sisodia, SS, and Tsien, JZ. (2001) Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron, 32, 911-926. Abstract

2. Wittenberg, GM, and Tsien, JZ. (2002). An emerging molecular and cellular framework for memory processing by the hippocampus. Trends in Neuroscience 25:10:501-505. Abstract

3. Wittenberg, GM, Sullivan M, and Tsien, JZ. (2002). Synaptic reentry reinforcement based network model for long-term memory consolidation. Hippocampus, 12, 637-647. Abstract

View all comments by Joe Tsien