Involvement of Cajal–Retzius cells in robust and layer‐specific regeneration of the entorhino‐hippocampal pathways

Abstract

Severed adult CNS axons can extend over long distances when a permissive 'milieu', such as grafted Schwann cells or ensheathing cells, is provided. Moreover, functional blocking of endogenous inhibitory factors, such as Nogo-A or proteoglycans, enhances the regeneration of axotomized neurons. Here we examine whether guidance cues available during the development of axonal pathways could also potentiate the regeneration of lesioned adult circuits. The Cajal-Retzius cells in the hippocampus are transient pioneer neurons that guide entorhino-hippocampal afferents to their target layers. By using an in vitro model of axotomy of the entorhino-hippocampal pathway we show that Cajal-Retzius cells triggered the regeneration of the axotomized entorhino-hippocampal pathway. Furthermore, the regrowth induced by Cajal-Retzius cells was robust and its pattern was indistinguishable from that of the unlesioned entorhino-hippocampal pathway. Thus, regenerating axons regrew in a layer-specific fashion towards the appropriate target layers, making synaptic contacts with target pyramidal neurons. Interestingly, the ability of lesioned entorhinal axons to regrow was maintained for at least 9 days after axotomy. These results show that the growth-promoting cells controlling the development of neural circuits will be a relevant approach to promoting the regeneration of lesioned adult CNS pathways.

Neurites regrowth of cortical neurons by GSK3β inhibition independently of Nogo receptor 1

“…Entorhino‐hippocampal slice co‐cultures from wild‐type and NgR1−/− mice were prepared from P0 (day of birth) or P1 mouse pups as described elsewhere (del Rio et al. 2002; del Rio and Soriano 2010).…”

“…After 15 DIV, the EHP of NgR1−/− and wild type was axotomized by cutting the co‐cultures from the rhinal fissure to the ventricular side along the entire entorhino‐hippocampal (EH) interface with a tungsten knife (see del Rio et al. 2002; for details).…”

“…1997). Some traced co‐cultures of NgR1−/− were processed for electron microscopy analysis as described (del Rio et al. 2002).…”

Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics

“…First, this provides evidence that organotypic slice cultures can be used as a valuable tool in studying post-lesion outgrowth since evidence shows that damaged axons can regenerate in a supportive environment [47,156,176]. Second, the contribution of excitotoxicity and synaptic firing to acute neuronal injuries, such as ischemia and traumatic injury, and its impact on the outcome of long-term recovery have to be examined with caution, since their involvement might have been over-accentuated in this model, compared to the native system.…”

Regenerating cortical connections in a dish: the entorhino-hippocampal organotypic slice co-culture as tool for pharmacological screening of molecules promoting axon regeneration

“…Though relevant, these methods do not bring the researcher close to the in vivo situation, since most factors in these preparations are lacking. The loss of regeneration of the EHC in vitro closely followed those seen in vivo 26,30,40 and most of the factors involved in the absence of regeneration are present in these culture platforms 29 . In technical terms, in our experience, TaueGFP cultures are more appropriate than Biocytin-labeled cultures for a fast evaluation of a molecular screening, since all possible regenerating axons will be fluorescent.…”