Research Group Ionic Currents in neuronal Development and Disease (PD Dr. Ulf Strauß)
- intrinsic and synaptic currents in developing neurons in striatum and cortex
- neuiroinflammation - neocortical excitability altered by cytokines
- altered ionic conductances in epilepsy, hypokinetic-rigid syndromes, autism spectrum diseases, microcephaly
- exploring emerging technical possibilities in cellular electrophysiology
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Impact of ionic currents (mediating cellular excitability and plasticity) on neuronal develpoment
Understanding neocortical development in relation to electrical activity implies unraveling conductances and their properties during early developmental time points.
Multipotent neural progenitor cells express Na+ channels in their membrane irrespective of their fate, but these channels have little effect due to their subunit composition that is regulated by alternative splicing. This indicates a mechanism locking developing cells in the multipotent progenitor stage through the control of neuronal excitability.
Developmental aspects of the hyperpolarization-activated, cyclic nucleotide-gated current (Ih)
We observed a robust perinatal occurrence of Ih and identified novel aspects of Ih characteristics in cortical plate neurons: cyclic AMP sensitivity is increased and the deactivation is slowed in a narrow perinatal time frame. The combination of these properties causes either a lack of neuronal membrane resonance or a shift to very low frequencies rendering them relevant for cortical network activity. The distinct functional features are related to the membrane appearance of HCN channels composed of phylogenetically old HCN subunits with slow kinetics. Though present in rather small amounts “fast” HCN1 subunits influence the kinetics of perinatal Ih. Early Ih properties appear to be temporally related to the occurrence of spontaneous synchronous activity in the neocortex, pointing to a role of Ih in a particular restricted critical developmental period. They may, on the other hand, render early Ih sensitive to perturbation with profound long-term consequences.
Cytokine actions on neurons
We identified HCN1 channels as a novel neural target for type I interferons (IFNs) providing the possibility to tune neural responses during the complex event of a CNS inflammation. Our experiments link the generation of inducible cytokines as IFNs and alterations in brain activity during CNS inflammations by showing that elevation of IFNs alters Ih and other intrinsic currents in cortical pyramidal neurons in vivo and in vitro. The effect requires an intact type I receptor signaling cascade and is PKC mediated. Consistent with Ih inhibition, IFNs affected neuronal membrane properties. In vivo application of IFN-β to rat and mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity. Currently we extend this approach to type II IFNs and synaptic activity.
Ion channels and disease
In a DFG funded project we currently investigate mechanisms of Chloride homeostasis in neuronal excitability, in particular its role in pharmacoresistant epilepsy.
In other collaborative approaches we unravel functional implications of certain molecular alterations, for instance we found miniature postsynaptic currents – the baseline electrical activity comprising spontaneous transmitter releases from single vesicles – altered under the influence of the phospholipid lysophosphatidic acid and in animals mimicking an autism spectrum disease (due to lacking NOMAGAP ) as well as in in a microcephaly model (Cdk5rap2 mutation).
Since synaptic currents are interlocked with proper neuronal development, this brings us full circle to our first topic.