Adult neurogenesis in the the hippocampus
The hippocampal formation within the medial temporal lobe of the cerebral cortex is essential for our conscious memory for facts and events. Remarkably, the hippocampus is one of the very few regions in the central nervous system of adult mammals, including humans, where new neurons are continuously generated throughout life. This indicates that the new neurons are involved in learning and formation of new memories. In support of this hypothesis, we previously found that newly generated young neurons show enhanced excitability and synaptic plasticity as compared to the neighboring mature cells.
Within the hippocampus neurogenesis is restricted to granule cells in the dentate gyrus (Fig.1). They receive excitatory inputs from the entorhinal cortex and project to the CA3 pyramidal cells. The dentate gyrus has some distinct structural features and is believed to serve distinct functions during memory processing. First of all, the granule cells form a so called competitive network as there is strong mutual inhibition via inhibitory GABAergic interneurons. By contrast, the CA3 pyramidal cells form an autoassociative network via mutually excitatory synaptic connections (Fig.1). Second, the number of granule cells (~1 million in the hippocampus of young adult rats) appears to be ~5-times larger than the number of afferent entorhinal layer II principal cells and ~3-times larger than the number of CA3 pyramidal cells in the output region. This form of expansion recoding within a competitive network generates a sparse and orthogonal (non-overlapping) representation, which helps to separate similar neuronal activity patterns – a function called “pattern separation”. As a consequence, each memory item can be stored within the hippocampal network in a unique fashion. Finally, new granule cells can be generated throughout life from adult neural stem cells located in the subgranular zone of the dentate gyrus (Fig. 2). Proliferation and differentiation of adult neural stem cells is tightly regulated in an activity dependent manner. Thus, the number of neurons might be adjusted to maintain sparse coding even with increasing memory load.
To understand signal processing in the dentate gyrus, we studied the func- tional properties of mature and newly generated granule cells (Stocca et al. 2008, Schmidt-Hieber and Bischofberger 2010) and the synaptic interaction with inhibitory GABAergic interneurons (Aponte et al. 2008, Buccurenciu et al. 2010). Using Ca2+ imaging in acute brain slices, we studied dendritic Ca2+ signals in young and mature granule cells evoked by backpropagating action potentials (Figure 3, Stocca et al. 2008). We found that the young neurons show remarkably large dendritic Ca2+ transients with slow decay time course. We could show that the slow decay of Ca2+ signals is due to low Expression levels of different Ca2+ pumps leading to ~10-times slower Ca2+ extrusion rates in young cells as compared to mature granule cells. Furthermore, the young neurons show a small Ca2+ buffer capacity. The Ca2+ binding ratio (in- crease in buffer-bound Ca2+ per increase in free Ca2+) in young cells was ~75 (versus ~220 in mature cells). Corresponding values published for pyramidal cells are ~100. The low Ca2+ buffer capacity in young cells together with the slow Ca2+ extrusion rate, might facilitate the generation of large Ca2+ signals important for dendritic growth and synaptic plasticity. By contrast, mature granule cells have a high Ca2+ buffer capacity more similar to GABAergic interneurons of the dentate gyrus (~200, Aponte et al. 2008). This might support stability of synaptic connections and restrict the activation of Ca2+ dependent processes in mature granule cells as well as in dentate gyrus interneurons to strong burst activity.
Further studies will help to understand the impact of these mechanisms on survival, differentiation and synaptic integration of the young cells into the adult neural network. This will not only be important for understanding learning and memory formation but might also help to develop future strategies for stem cell therapies after stroke and neurodegenerative diseases.