Homeostatic Intrinsic Plasticity Is Functionally Altered in Fmr1 KO Cortical Neurons

• Published in: Cell reports (Cambridge) 2019-02, Vol.26 (6), p.1378-1388.e3
• Main Authors: Bülow, Pernille, Murphy, T.J., Bassell, Gary J., Wenner, Peter
• Format: Article
• Language: English
• Subjects: Animals; autism; Cerebral Cortex - cytology; Cerebral Cortex - physiopathology; compensatory; cortical cultures; excitability; Fragile X Mental Retardation Protein - genetics; fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - physiopathology; Homeostasis; homeostatic plasticity; K channels; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Na channels; Neuronal Plasticity; Neurons - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.01.035

Cortical hyperexcitability is a hallmark of fragile X syndrome (FXS). In the Fmr1 knockout (KO) mouse model of FXS, cortical hyperexcitability is linked to sensory hypersensitivity and seizure susceptibility. It remains unclear why homeostatic mechanisms fail to prevent such activity. Homeostatic intrinsic plasticity (HIP) adjusts membrane excitability through regulation of ion channels to maintain activity levels following activity perturbation. Despite the critical role of HIP in the maturation of excitability, it has not been examined in FXS. Here, we demonstrate that HIP does not operate normally in a disease model, FXS. HIP was either lost or exaggerated in two distinct neuronal populations from Fmr1 KO cortical cultures. In addition, we have identified a mechanism for homeostatic intrinsic plasticity. Compromising HIP function during development could leave cortical neurons in the FXS nervous system vulnerable to hyperexcitability. [Display omitted] •Activity block normally drives conversion of single- to multi-spiking neurons•Fmr1 knockout (KO) neurons fail to convert single- to multi-spiking neurons•Multi-spiking Fmr1 KO neurons display exaggerated compensatory increase in spiking•Altered homeostatic intrinsic plasticity may contribute to hyperexcitability in FXS Fragile X syndrome (FXS) is characterized by cortical hyperexcitability, but the mechanisms driving hyperexcitability are poorly understood. Homeostatic intrinsic plasticity (HIP) regulates ion channel function to maintain appropriate activity levels. Bülow et al. show that HIP is functionally altered in FXS neurons, which may leave cortical neurons vulnerable to hyperexcitability.