Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice.

Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice. Neuropharmacology. 2018 Jun 08;: Authors: Jewett KA, Lee KY, Eagleman DE, Soriano S, Tsai NP Abstract Chronic activity perturbations in neurons induce homeostatic plasticity through modulation of synaptic strength or other intrinsic properties to maintain the correct physiological range of excitability. Although similar plasticity can also occur at the population level, what molecular mechanisms are involved remain unclear. In the current study, we utilized a multielectrode array (MEA) recording system to evaluate homeostatic neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic elevation of neuronal activity through the inhibition of GABA(A) receptors elicits synchronization of neural network activity and homeostatic reduction of the amplitude of spontaneous neural network spikes. We subsequently showed that this phenomenon is mediated by the ubiquitination of tumor suppressor p53, which is triggered by murine double minute-2 (Mdm2). Using a mouse model of fragile X syndrome, in which fragile X mental retardation protein (FMRP) is absent (Fmr1 knockout), we found that Mdm2-p53 signaling, network synchronization, and the reduction of network spike amplitude upon chronic activity stimulation were all impaired. Pharmacologically inhibiting p53 with Pifithrin-α or genetically employing p53 heterozygous m...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research