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

Kathryn A. Jewett, Kwan Young Lee, Daphne E. Eagleman, Stephanie Soriano, Nien-Pei Tsai

Research output: Contribution to journalArticle

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 mice to enforce the inactivation of p53 in Fmr1 knockout cultures restored the synchronization of neural network activity after chronic activity stimulation and partially corrects the homeostatic reduction of neural network spike amplitude. Together, our findings reveal the roles of both Fmr1 and Mdm2-p53 signaling in the homeostatic regulation of neural network activity and provide insight into the deficits of excitability homeostasis seen when Fmr1 is compromised, such as occurs with fragile X syndrome.

Original languageEnglish (US)
Pages (from-to)182-192
Number of pages11
JournalNeuropharmacology
Volume138
DOIs
StatePublished - Aug 2018

Fingerprint

Fragile X Syndrome
Fragile X Mental Retardation Protein
Neurons
Ubiquitination
GABA-A Receptors
Homeostasis
Population
Neoplasms

Keywords

  • Fmr1
  • FXS
  • Mdm2
  • Neural network
  • p53
  • Plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice. / Jewett, Kathryn A.; Lee, Kwan Young; Eagleman, Daphne E.; Soriano, Stephanie; Tsai, Nien-Pei.

In: Neuropharmacology, Vol. 138, 08.2018, p. 182-192.

Research output: Contribution to journalArticle

Jewett, Kathryn A. ; Lee, Kwan Young ; Eagleman, Daphne E. ; Soriano, Stephanie ; Tsai, Nien-Pei. / Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice. In: Neuropharmacology. 2018 ; Vol. 138. pp. 182-192.
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