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
- Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004 May 27;42(4):535-52. PubMed.