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