Abstract
Sprouting of surviving axons is one of the major reorganization mechanisms of the injured brain contributing to a partial restoration of function. Of note, sprouting is maturation as well as age-dependent and strong in juvenile brains, moderate in adult and weak in aged brains. We have established a model system of complex organotypic tissue cultures to study sprouting in the dentate gyrus following entorhinal denervation. Entorhinal denervation performed after 2 weeks postnatally resulted in a robust, rapid, and very extensive sprouting response of commissural/associational fibers, which could be visualized using calretinin as an axonal marker. In the present study, we analyzed the effect of maturation on this form of sprouting and compared cultures denervated at 2 weeks postnatally with cultures denervated at 4 weeks postnatally. Calretinin immunofluorescence labeling as well as time-lapse imaging of virally-labeled (AAV2-hSyn1-GFP) commissural axons was employed to study the sprouting response in aged cultures. Compared to the young cultures commissural/associational sprouting was attenuated and showed a pattern similar to the one following entorhinal denervation in adult animals in vivo. We conclude that a maturation-dependent attenuation of sprouting occurs also in vitro, which now offers the chance to study, understand and influence maturation-dependent differences in brain repair in these culture preparations.
Highlights
The reorganization of denervated brain regions is seen in many pathological conditions in which some form of structural damage has occurred (Steward, 1991; Deller and Frotscher, 1997; Perederiy and Westbrook, 2013)
A local lesion of the brain is not really ‘‘local’’ but rather the spot where the neuronal network has been disrupted. Neurons respond to this challenge to the network by rewiring their connections aiming at re-establishing homeostasis and information throughput (Steward, 1994; Vlachos et al, 2012a,b, 2013a; Willems et al, 2016; Yap et al, 2020). This may eventually result in a partial restoration of function, which may even be strengthened by training or specific rehabilitation techniques (Fawcett, 2009; Garcia-Alias et al, 2009; Maier et al, 2009; Martin, 2012; Filli and Schwab, 2015)
We previously demonstrated that calretininimmunofluorescence can be used to quantify collateral sprouting of commissural-associational mossy cell axons after entorhinal denervation (Del Turco et al, 2019)
Summary
The reorganization of denervated brain regions is seen in many pathological conditions in which some form of structural damage has occurred (Steward, 1991; Deller and Frotscher, 1997; Perederiy and Westbrook, 2013). A local lesion of the brain is not really ‘‘local’’ but rather the spot where the neuronal network has been disrupted Neurons respond to this challenge to the network by rewiring their connections aiming at re-establishing homeostasis and information throughput (Steward, 1994; Vlachos et al, 2012a,b, 2013a; Willems et al, 2016; Yap et al, 2020). This may eventually result in a partial restoration of function, which may even be strengthened by training or specific rehabilitation techniques (Fawcett, 2009; Garcia-Alias et al, 2009; Maier et al, 2009; Martin, 2012; Filli and Schwab, 2015). Beneficial effects of sprouting include restoring a denervated neuron to its physiological firing range, maintaining the dendritic arbor of a denervated neuron, and, in the case of sprouting axons that are homologous to those that were lost, restoration of information flow (Steward, 1991; Deller and Frotscher, 1997)
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