Kurzfassung

During early development, a substantial proportion of central neurons undergoes programmed cell death. This fundamental homeostatic process controlling the ultimate number of neurons is essential for the proper structural and functional development of the brain. Neuronal activity has a major impact on neuronal death and survival rates in developing cortical networks. While blockade of neuronal activity profoundly increases cellular mortality rate, an increase in neuronal activity is generally...During early development, a substantial proportion of central neurons undergoes programmed cell death. This fundamental homeostatic process controlling the ultimate number of neurons is essential for the proper structural and functional development of the brain. Neuronal activity has a major impact on neuronal death and survival rates in developing cortical networks. While blockade of neuronal activity profoundly increases cellular mortality rate, an increase in neuronal activity is generally associated with a decline in neuronal death. Although a better understanding of these activity-dependent regulatory mechanisms as well as their importance for brain development is emerging, many critical questions about this fundamental developmental process remain open.

During the last two funding periods we have shown how neuronal activity controls apoptosis induction in distinct neuronal cell types destined to die during early corticogenesis (e.g. Cajal-Retzius neurons). Moreover, we could show that electrical activity tunes the final number of surviving neurons in the developing cortex in a region-specific manner. Thus, activity homeostatically regulates the population size of developing neuronal networks in a region- and time-dependent manner. At the single-cell level, we demonstrated that not only action potential firing per se acts as a pro-survival factor in early development, but also the specific temporal discharge pattern controls neuronal survival. Synchronized spindle burst activity, which represents a characteristic feature of the perinatal cerebral cortex in all mammalian species studied so far (from mouse to humans), fulfil a physiologically relevant role in the control of cell survival vs. cell death. In summary, our previous studies showed that activity-dependent modulation of neuronal survival occurs (i) at the level of functional regions in the developing cortex, (ii) at the level of single neurons in cortical cultures and even (iii) as indicated by on-going experiments at the subcellular level of the neuronal nucleus.

In the third funding period, we propose to study (1) the molecular mechanisms that translate patterned electrical activity into cell death versus survival decisions and how they are reflected in nano-structural changes in the cell nucleus. At the network level, physiological versus non-physiological as well as local versus global changes in cortical activity determine the spatio-temporal extent of apoptosis. This implies that activity during early development directly affects ultimate population sizes in the mature cortex. Therefore, the second major aim of this proposal (2) is to address the impact of altered cell death on neuronal network activity in the developing somatosensory cortex and on the functional of the adult cortex.

In summary, the results of these planned experiments will provide a better understanding of activity-dependent apoptosis as important homeostatic element at the network, cellular and subcellular level during early development. Moreover, these data will expand our knowledge on how this developmental process shapes both the structure and the function of the mature nervous system.» weiterlesen» einklappen