BBB Seminar: Thomas Deller
Dendritic remodelling after axonal denervation
Thomas Deller, Department of Clinical Neuroanatomy, Goethe-University of Frankfurt, Frankfurt am Main, Germany
The CNS reacts to injury with a remodelling of neuronal connections. Although little repair occurs at injury sites (regeneration failure), denervated areas of the brain show extensive axonal and dendritic reorganization (collateral sprouting; reactive synaptogenesis; dendritic remodelling). This denervation-induced plasticity is believed to underlie the functional recovery observed after small brain injuries and provides the neurobiological basis for rehabilitative programs for patients suffering from CNS damage.
Although neuronal reorganization after injury has been described many years ago, little is known about its dynamics and the underlying molecular mechanisms. To study the reorganization of neurons after denervation, mature organotypic slice cultures (OTCs) of mouse entorhinal cortex and hippocampus can be employed. In these cultures the entorhinal projection to the hippocampus develops organotypically and can be readily transected. Imaging methods (confocal microscopy and 2-photon microscopy) can be used to visualize and follow structural as well as metabolic changes after denervation.
We used OTCs of Thy1-eGFP mice to study the dendritic reorganization of granule cells after entorhinal denervation. In these cultures a subpopulation of granule cells are eGFP-positive, which makes it possible to image granule cells over several weeks and to visualize dendritic changes. Using time-lapse confocal imaging we studied degeneration of granule cell dendrites as well as changes in spine density, spine loss, and spine formation. On the basis of our data we propose a novel model of spine plasticity after denervation.
Finally, we analyzed the mechanisms that could underlie dendritic reorganization after denervation. Since it has been proposed that dendritic degeneration could be caused by an excess release of glutamate from severed axon terminals, which, in turn, leads to a toxic influx of Ca2+ into the denervated neurons, we visualized intracellular Ca2+ levels of granule cells during and after entorhinal denervation. Our data indicate that direct damage to granule cell dendrites but not axonal denervation alone causes toxic elevations of intracellular Ca2+-levels. Thus, denervation-induced dendritic plasticity is likely to be regulated by other signals (e.g. loss of activity, loss of cell-adhesion, loss of neurotrophic support).
Host: Clive Bramham (firstname.lastname@example.org), Department of Biomedicine