Network function of early born glutamatergic neurons in health and disease
Final Report Abstract
The key hypothesis of this proposal was that glutamatergic cells born early in embryogenesis display specific morpho-physiological properties and connectivity patterns that enable them to exert a specific role in orchestrating physiological or pathological network dynamics. In addition, we expect that these pioneer cells preferentially form interconnected microcircuits with a high functional network impact and that an early birthdate confers onto them a selective resistance to pathological insults. The project planned to test these hypotheses on two types of glutamatergic neurons from the hippocampus (1) semilunar DG granule cells, a poorly described canonical subtype of granule cells which exerts a powerful network influence, and (2) the CA1 pyramidal cell, the most commonly studied subtype of glutamatergic neuron in the brain. Moreover, the diversity was to be analysed in the context of a major common chronic brain disorder, temporal lobe epilepsy (TLE). Analyzing the complex network changes occurring in TLE and PD from the point of view of development, should unravel specific microcircuits that might preferentially act on pathological neuronal ensemble activity. In the initial phase of the project, we intended to import into our animal house the transgenic mouse strains necessary for the project, which are necessary for genetic labeling of the prematurely born glutamatergic cell types. Unfortunately, in the meantime, contamination of the animal house in Marseilles had occurred, which made the direct transfer of NGN2-CreERTM; RCE mice impossible. Due to the problems encountered, despite our best efforts, it was not possible to initiate first experiments with NGN2-CreERTM; RCE mice crossed with reporter lines. We therefore endeavored to examine key features of CA1 and dentate circuits with the techniques and approaches outlined in the proposal, but at somewhat more detail than initially planned. The main results can be summarized as follows: CA1 dendritic excitability changes in epilepsy: We found that dendritic spiking is upregulated in 1st order CA1 dendrites in chronic epilepsy, and have identified the Nav1.3 sodium channel as one key player in this phenomenon. In-vivo analyses are running to see how this mechanism affects place coding of CA1 neurons, as well as spatial memory. - GC activity patterns in-vivo: dual color 2P in-vivo imaging established for the project revealed a novel population activity of GCs in animals during quiet immobility that is highly structured and may be a correlate of working memory. - GC network analysis: We have carefully determined the quantitative spatiotemporal features of canonical feedback inhibition. We have built a computational model, and have generated the prediction that a selective boosting of pattern separation for highly similar input patterns occurs during slow-gamma oscillations (see manuscript attached). - Contribution towards generation of a potassium channel based optogenetic silencing too.
Publications
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(2018) Potassium channelbased optogenetic silencing. Nat. Communications, 9: 4611
Bernal-Sierra, Y-A., Rost, B.R., Pofahl, M., Fernandes, A.M., Kopton, R.A., Holtkamp, D., Masala, N., Beed, P., Tukker, J.J., Oldani, S., Bönigk, W., Kohl, P., Baier, H., Schneider-Warme, F., Hegemann, P., Beck, H., Seifert, R., Schmitz, D.
