Abstract
BackgroundNeural network synchrony is a critical factor in regulating information transmission through the nervous system. Improperly regulated neural network synchrony is implicated in pathophysiological conditions such as epilepsy. Despite the awareness of its importance, the molecular signaling underlying the regulation of neural network synchrony, especially after stimulation, remains largely unknown.ResultsIn this study, we show that elevation of neuronal activity by the GABA(A) receptor antagonist, Picrotoxin, increases neural network synchrony in primary mouse cortical neuron cultures. The elevation of neuronal activity triggers Mdm2-dependent degradation of the tumor suppressor p53. We show here that blocking the degradation of p53 further enhances Picrotoxin-induced neural network synchrony, while promoting the inhibition of p53 with a p53 inhibitor reduces Picrotoxin-induced neural network synchrony. These data suggest that Mdm2-p53 signaling mediates a feedback mechanism to fine-tune neural network synchrony after activity stimulation. Furthermore, genetically reducing the expression of a direct target gene of p53, Nedd4-2, elevates neural network synchrony basally and occludes the effect of Picrotoxin. Finally, using a kainic acid-induced seizure model in mice, we show that alterations of Mdm2-p53-Nedd4-2 signaling affect seizure susceptibility.ConclusionTogether, our findings elucidate a critical role of Mdm2-p53-Nedd4-2 signaling underlying the regulation of neural network synchrony and seizure susceptibility and reveal potential therapeutic targets for hyperexcitability-associated neurological disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0214-6) contains supplementary material, which is available to authorized users.
Highlights
Neural network activity modulates the efficacy of synaptic transmission, and proper regulation of neural network activity, such as through the modulation of synchronization, has been shown to be important in development [1], learning and memory [2], and disease such as epilepsy [3]
Murine Double Minute-2 (Mdm2)-p53 signaling provides feedback modulation for neural network synchrony during chronic elevation of neuronal activity With the intent of studying the role of Mdm2-p53 signaling in the regulation of neural network synchrony (Fig. 1a), we used an multielectrode array (MEA) to record extracellular spontaneous spikes of cultured primary mouse cortical neurons (Fig. 1b)
To determine whether and how neural network synchrony was regulated after stimulation in cultured neurons, we applied a widely used method to elevate neuronal activity; we treated primary mouse (C57BL/6) cortical neuron cultures with the GABA(A) receptor antagonist Picrotoxin (PTX, 100 μM) [13, 14]
Summary
Neural network activity modulates the efficacy of synaptic transmission, and proper regulation of neural network activity, such as through the modulation of synchronization, has been shown to be important in development [1], learning and memory [2], and disease such as epilepsy [3]. One promising pathway involving the feedback, or inhibitory, regulation of network activity after stimulation is Mdm2-p53-Nedd signaling [6]. When neuronal activity is chronically elevated, phosphorylation of the E3 ligase, Murine Double Minute-2 (Mdm2) leads to the down-regulation of its substrate, p53. Nedd is an epilepsy-associated gene [8] encoding a ubiquitin E3 ligase with many membrane receptor and ion channel targets [6, 9, 10]. Despite the awareness of its importance, the molecular signaling underlying the regulation of neural network synchrony, especially after stimulation, remains largely unknown
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