NMDA-receptor inhibition increases spine stability of denervated mouse dentate granule cells and accelerates spine density recovery following entorhinal denervation in vitro

作者：Vlachos Andreas^*; Helias Moritz; Becker Denise; Diesmann Markus; Deller Thomas

来源：Neurobiology of Disease, 2013, 59: 267-276.

DOI：10.1016/j.nbd.2013.07.018

• Entorhinal cortex lesion
• Homeostatic synaptic plasticity
• Synaptic scaling
• Neurorestauration
• Regeneration
• Memantine
• Amantadine

Neuronal networks are reorganized following brain injury. At the structural level this is in part reflected by changes in the spine turnover of the denervated neurons. Using the entorhinal cortex lesion in vitro model, we recently showed that mouse dentate granule cells respond to entorhinal denervation with coordinated functional and structural changes: During the early phase after denervation spine density decreases, while excitatory synaptic strength increases in a homeostatic manner. At later stages spine density increases again, and synaptic strength decreases back to baseline. In the present study, we have addressed the question of whether the denervation-induced homeostatic strengthening of excitatory synapses could not only be a result of the deafferentation, but could, in turn, affect the dynamics of the spine reorganization process following entorhinal denervation in vitro. Using a computational approach, time-lapse imaging of neurons in organotypic slice cultures prepared from Thy1-GFP mice, and patch-clamp recordings we provide experimental evidence which suggests that the strengthening of surviving synapses can lead to the destabilization of spines formed after denervation. This activity-dependent pruning of newly formed spines requires the activation of N-methyl-D-aspartate receptors (NMDA-Rs), since pharmacological inhibition of NMDA-Rs resulted in a stabilization of spines and in an accelerated spine density recovery after denervation. Thus, NMDA-R inhibitors may restore the ability of neurons to form new stable synaptic contacts under conditions of denervation-induced homeostatic synaptic up-scaling, which may contribute to their beneficial effect seen in the context of some neurological diseases.

• 出版日期2013-11