Abstract
Increasing evidence suggests that pathological hallmarks of chronic degenerative syndromes progressively spread among interconnected brain areas in a disease-specific stereotyped pattern. Functional brain imaging from patients affected by various neurological syndromes such as traumatic brain injury and stroke indicates that the progression of such diseases follows functional connections, rather than simply spreading to structurally adjacent areas. Indeed, initial damage to a given brain area was shown to disrupt the communication in related brain networks. Using cortico-striatal neuronal networks reconstructed in a microfluidic environment, we investigated the role of glutamate signaling in activity-dependent neuronal survival and trans-synaptic degeneration processes. Using a variety of neuronal insults applied on cortical neurons, we demonstrate that acute injuries such as axonal trauma, focal ischemia, or alteration of neuronal rhythms, lead to glutamate-dependent striatal neuron dysfunction. Interestingly, focal pro-oxidant insults or chronic alteration of spontaneous cortical rhythms provoked dysfunction of distant striatal neurons through abnormal glutamate GluN2B-NMDAR-mediated signaling at cortico-striatal synapses. These results indicate that focal alteration of cortical functions can initiate spreading of dysfunction along neuronal pathways in the brain, reminiscent of diaschisis-like processes.
Highlights
Diaschisis is defined as a dysfunction in an area of the brain connected to a distant, damaged, brain area[1]
Corroborating previous work on brain slices, we found that axotomy of cortical fibers induced trans-synaptic striatal neuron degeneration that was mainly due to NMDA receptors (NMDAR)-mediated excitotoxicity, rather than “passive” loss of presynaptic input
Blockade of GluN2A-containing NMDARs with NVP (50 nM or 500 nM), or with 10 μM TCN-201 showed no protective effect, while inhibition of striatal GluN2B-containing NMDARs with 10 μM of Ifenprodil, or 10 μM RO-256981 completely reversed the deleterious effect (Fig. 4e). These results suggest that abnormal glutamatergic transmission following cortical extrasynaptic NMDAR stimulation leads to progressive GluN2B-NMDAR-mediated trans-synaptic pruning of distant striatal neurons
Summary
Diaschisis is defined as a dysfunction in an area of the brain connected to a distant, damaged, brain area[1]. The primary mechanisms of diaschisis are functional and structural deafferentiation that lead to loss of input information from the damaged brain area. This is followed at later stages by reorganization of distributed brain networks in the distantly targeted area[2,3,4]. The molecular mechanisms of trans-synaptic degeneration processes have been studied using organotypic brain slices and axonal trauma paradigms[20,21]; using these methods, unravelling the molecular consequences of focal and chronic insults on distant connected brain areas remains a challenging issue, and calls for the development of new experimental tools. Our results, which are reminiscent of diaschisis-like processes, indicate that chronic alteration of neuronal rhythmic patterns can initiate the spreading of neuronal degeneration processes along a neuronal network
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