CRA2 Neuronal Stress

Coordinator: Britta Qualmann

Signalling pathways in neurons do not follow a simple linear dose-response. Cellular responses to synaptic transmission are strongly dependent on dose and frequency of stimulation (neurohormesis). Low to medium doses of the major excitatory neurotransmitter glutamate mediate synaptic transmission and plasticity, learning and memory - such doses activate adaptive cellular stress response pathways from which nerve cells benefit, promoting their growth and survival. Importantly, different stimulation paradigms are hereby known to result either in an increase or decrease of synaptic strength resulting in long term potentiation (LTP) or depression (LTD) - two important mechanisms behind learning and memory. However, excessive amounts of glutamate can damage and kill nerve cells. This toxic process is caused by the massive Ca2+ influx, called excitotoxicity and occurs during severe epileptic seizures and stroke. CRA2 therefore aims at unveiling the molecular signalling mechanisms underlying neurotransmitter dose- and time-dependent alterations of synaptic transmission, synaptic plasticity and neuronal survival.
Synaptic adaptive processes involve careful spatial control of signalling cues such as phosphoinositides. We therefore propose to directly visualise and quantify spatial and temporal correlations of the lipid signals, the signal-generating enzyme such as PI3K and their putative effectors under different doses of neurotransmitter-induced signalling stress.
Adaptive responses in neurons require morphological alterations in cell shape controlled by the actin cytoskeleton underlying the plasma membrane. An additional focus will therefore be to address the effects of dose-dependent glutamate and particularly Ca2+-mediated signalling on cytoskeletal-driven structural and functional adaptations in neurons under physiological as well as excitotoxic conditions. During the first funding period, work in the CRA2 had identified the Ca2+-concentration-dependent complex formation of an actin nucleator, Cobl, with calmodulin, an important calcium sensor protein. In sharp contrast to the positive effects of moderate Ca2+ and glutamate signalling effects, stroke-induced glutamate accumulation mediates a detrimental Ca2+ influx into cells, excitotoxicity. As a causal link between ischemia and neuronal death, excitotoxic processes are targets in the prevention of stroke damage and further studies will therefore address a role of Cobl as calcium-dependent target in excitotoxicity induced by ischemic stroke. Additionally, we aim at providing insights into healthy brain ageing by studying control mechanisms of Ras activity in neural stem cells. This adaptive signalling pathway has been suggested to respond to exercise and caloric restriction and may thereby promote the brain's resistance to ageing-dependent degeneration and improve brain regeneration after stroke. Finally, we will deepen our exciting studies from the first funding period on the identification of a key receptor that controls endoplasmic reticulum turnover in response to different stress stimuli via autophagic degradation and its pathophysiological role in the degeneration of sensory neurons in a disorder entitled hereditary sensory autonomic neuropathy type II.