Research presented in the May 27 issue of Neuron supports links between ongoing excitatory activity in the neural networks of the hippocampus and adult neurogenesis. Indeed, suggest the authors, this mechanism could underlie both the storage and clearance of memories.

Accumulated experimental evidence makes it reasonable to suspect that the ongoing birth of new neurons in the adult hippocampus is related to the encoding, storage, and management of memory. Researchers also suspect that the rate of neurogenesis is in some way controlled by activity in this neural network, though there is scant evidence of this and some of the evidence appears contradictory. For the Alzheimer's community, hippocampal neurogenesis is of particular interest for the possibility that neuronal proliferation could one day be clinically upregulated to boost failing memory systems (see ARF Live Discussion).

Karl Deisseroth and Robert Malenka of Stanford University, in collaboration with Theo Palmer's group, also at Stanford, report on a series of experiments designed to get at the complex question of whether activity in hippocampal networks might affect the birth of new neurons in the adult hippocampus, and if so, how this would happen.

Deisseroth and colleagues worked at first with hippocampal slice preparations, in which electrophysiological processes can be kept ‘alive’ for several weeks. Mimicking excitatory input with extracellular potassium, the researchers found that in a population of exogenous neural precursor cells (NPCs) they had co-plated with the slice, this excitation led to increases in neurogenesis. This was not simply a general increase in cell division, rather, the ratio of neuronal and glial cells generated from the NPCs shifted toward neurons. The cells generated by this activity appeared to be fully functioning neurons, judging by their morphology, the expression of the neuronal proteins MAP2ab and Doublecortin, and the finding that they incorporate synapses into active neural circuits, the scientists report.

In a second round of experiments, Deisseroth and colleagues set out to investigate whether the excitation in the slice preparation acted on the NPCs directly. Alternatively, the signal might come through intermediaries, such as hippocampal neurons responding to the excitation and releasing growth factors. The researchers employed a clever set-up that might be called a "dead" slice preparation—they fixed the brain slice with ethanol, killing the intrinsic neurons, and then added live NPCs. Surprisingly, the precursors can survive and generate neural cells in this environment. Perhaps even more surprisingly, the researchers were able to replicate the excitation-induced neurogenesis seen in the "live" slices, indicating that mature cells are not needed to convey excitatory signals to the NPCs. Both extracellular K+ and the excitatory neurotransmitter glutamate boosted neurogenesis.

How did the excitation make its way into the precursor cell? The authors report that calcium signaling is the likely suspect, as excitatory stimulation increased signaling through voltage-gated calcium channel, particularly the Ca[v]1.2/1.3 channel variety. NMDA receptor channels were also capable of transducing the K+ excitation and induce neurogenesis. "NPCs themselves can act as the signal detection and processing elements mediating adult excitation-neurogenesis coupling," conclude the authors.

What happens next inside the precursor cell? The researchers found that Ca influx through NMDA and Ca[v]1.2/1.3 channels only 2 to 6 hours later led to downregulation of HES and Id2, two basic-helix-loop-helix (bHLH) genes that help suppress the neuronal phenotype in the precursors. Conversely, the bHLH gene NeuroD, which promotes neuronal differentiation, was upregulated.

To bolster these in-vitro results, Deisseroth and colleagues show evidence that Ca channel antagonists administered to mice increase hippocampal neurogenesis, and Ca channel agonists increase neurogenesis. The drug diazepam, which reduces hippocampal activity, downregulated neurogenesis.

The researchers conclude with a discussion of neural network models relevant to memory modeling. Previous work has been confusing, suggesting that adult neurogenesis in the hippocampus could underlie either storage of memories or clearance of old memories. The excitation-neurogenesis coupling shown in these experiments could, in fact, underlie both memory storage and clearance in a layered Hebbian network, write the authors. (For full details of the model, see supplementary materials for the paper.)—Hakon Heimer

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  1. 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:

    . Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004 May 27;42(4):535-52. PubMed.

    . Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.

    . NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab. 2000 Dec;20(12):1669-80. PubMed.

    . Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol. 2003 Sep;2(9):539-47. PubMed.

  2. 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:

    . 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. PubMed.

    . An emerging molecular and cellular framework for memory processing by the hippocampus. Trends Neurosci. 2002 Oct;25(10):501-5. PubMed.

    . Synaptic reentry reinforcement based network model for long-term memory consolidation. Hippocampus. 2002;12(5):637-47. PubMed.

References

Other Citations

  1. ARF Live Discussion

External Citations

  1. supplementary materials

Further Reading

Primary Papers

  1. . Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004 May 27;42(4):535-52. PubMed.