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 CNS 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 (Schmidt-Hieber et al. 2004, Nature 429:184-187).
Within the hippocampus neurogenesis is restricted to granule cells in the dentate gyrus (Figure 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 mutu- ally excitatory synaptic connections (Figure 1). Second, the number of granule cells 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 will generate a sparse and orthogonal (non-overlapping) representation, which will help 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 (Figure 2). Proliferation and differentiation of adult neural stem cells is tightly regulated in an activity dependent manner, indicating that the number of neurons might be adjusted to maintain sparse coding even with increasing memory load.
During the last three years we have focused on the process of synapse formation and synaptic integration of developing newly generated granule cells into the hippocampal circuitry. As extrasynaptic NMDA receptors are believed to support the generation of new spines, we have studied the functional properties of extrasynaptic ionotropic glutamate receptors in newly generated granule cells during and after synaptic integration (Schmidt- Salzmann et al. 2014, J Physiol 592: 125-140). Using fast application of glutamate to outside-out membrane patches, we showed that all immature granule cells express al- ready functional AMPA and NMDA receptors. The density of AMPA receptors was small in cells starting to receive excitatory synaptic input (~30 pS/ μm2) but substantially increased during synaptic integration to finally reach ~120 pS/μm2 in fully mature cells. Interestingly, AMPA receptors showed a biphasic change in desensitisation time constant which was slowest during synaptic integration and substantially faster before and afterwards. This was paralleled by a biphasic change in the non-desensitising current component which was maximal during synaptic integration and about two times smaller in fully mature granule cells. Surprisingly, the NMDA-receptor density in young cells was already similar to mature cells (~10 pS/μm2) and remained relatively constant throughout maturation. Also, functional properties of ex- trasynaptic NMDA-receptors were similar at different developmental stages. These data indicate that the non-desensitising AMPAR currents in newly generated young granule cells might support the effective activation of extrasyn- aptic NMDA receptors to induce Ca2+ influx and Ca2+-dependent activation of Rho-GTPases important for new spine formation. Together with the low Ca2+-buffer capacity in young neurons (Stocca et al. 2008, J Physiol 586:3795-3811; Pohle and Bischofberger, 2014, doi: 10.1113/jphysiol.2014.281931), the large AMPA-currents might constitute a competitive advantage over mature cells for new synapse formation.