Summary: A recent study uncovers a different mechanism contributing to neuronal hyperexcitability in fragile X syndrome and points to new, more specific treatment targets.
Source: WUSTL.
In wake of clinical trial failure, new treatment targets identified
For years researchers believed that fragile X syndrome, the most common inherited cause of intellectual disability in the United States and a significant known contributor to autism, was primarily driven by overactivity in a single brain signaling pathway. That view prompted large multinational clinical trials in 2014 that attempted to treat fragile X by blocking that pathway. Those trials ultimately failed to improve symptoms, signaling the need to reconsider underlying mechanisms and therapeutic strategies.
Researchers at Washington University School of Medicine in St. Louis now report an alternative explanation for some core features of fragile X syndrome. Published in Cell Reports, the study offers a fresh perspective on the biological changes that cause neuronal hyperexcitability in fragile X and identifies new molecular targets that may be more effective and better tolerated in patients.
“We found another pathway that is dysregulated, involving the same molecule previously implicated — mGluR5 — but operating in a fundamentally different way,” said Vitaly Klyachko, PhD, associate professor of cell biology and physiology and senior author of the study. “The earlier theory was not wrong, but the biology is more complex than previously appreciated.”
Fragile X syndrome affects roughly 1 in 4,000 people worldwide. Around 30 percent of individuals with fragile X are also diagnosed with autism, and fragile X is estimated to cause up to 6 percent of autism cases, making it the most common known single-gene cause of autism. A hallmark of fragile X is neuronal hyperexcitability: brain circuits respond too readily to stimulation, producing excess electrical activity.
Hyperactive circuits can cause seizures and heightened sensitivity to sensory stimuli, including sound, light and touch—symptoms common to both fragile X and many forms of autism. Fragile X results from mutations that eliminate fragile X mental retardation protein (FMRP). Without FMRP, the regulation of several proteins involved in neuronal signaling is lost, leading to abnormal protein levels and altered neuronal function. One such protein is mGluR5, a receptor for the neurotransmitter glutamate. Earlier treatments targeted mGluR5 based on the idea that its overactivity drives excessive neuronal responses, but clinical inhibition of mGluR5 did not yield the expected clinical benefits.
In the new study, Klyachko and Pan-Yue Deng, MD, PhD, assistant professor of cell biology and physiology, identify a distinct mechanism that produces neuronal hyperexcitability: an increase in the persistent, baseline flow of sodium ions into neurons. Using a well-established fragile X mouse model (Fmr1 knockout mice), the team measured electrical properties of neurons in the entorhinal cortex and found that these neurons have a lowered action potential threshold and are more excitable than normal.
The researchers determined that increased persistent sodium current (INaP) underlies the reduced action potential threshold. In neurons from Fmr1 knockout mice, mGluR5 actively signals through a downstream PLC–PKC (phospholipase C–protein kinase C) pathway to modify sodium channels so they remain open longer, allowing excessive sodium influx. That persistent sodium flow makes it easier for neurons to reach the threshold for firing an action potential, thus promoting hyperexcitability.
“The persistent sodium current is elevated, so it’s much easier for neurons to cross the firing threshold,” Klyachko explained. “The surprising element is that this effect depends on mGluR5, but through a different mechanism than previously proposed. This reconciles earlier findings that implicated mGluR5 in hyperexcitability while offering a new, more precise target.”
Importantly for treatment development, drugs that specifically reduce persistent sodium current are already approved by the U.S. Food and Drug Administration for epilepsy. Because these agents act directly on sodium current rather than broadly inhibiting mGluR5—which is a widely expressed molecule with many roles—targeting INaP could offer a more specific approach with fewer off-target effects. Klyachko and colleagues are initiating collaborative studies to test whether these sodium-current–targeting drugs can normalize persistent sodium flow and reduce hyperexcitability in fragile X models, with the long-term goal of translating positive results to patients.
Funding: This work was supported in part by the National Institute of Neurological Disorders and Stroke, grant number R01 NS081972.
Source: Tamara Bhandari – WUSTL
Image credit: Michael Worful
Original research: Deng, P.-Y. and Klyachko, V. A., “Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice,” Cell Reports, published online September 20, 2016 (open access).
Abstract
Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout mice
Highlights
• Action potential threshold is decreased in entorhinal cortex layer III pyramidal neurons of Fmr1 knockout mice
• Threshold changes are caused by increased persistent sodium current (INaP)
• The abnormal threshold is mediated by increased mGluR5–PLC–PKC pathway signaling
Summary
Altered neuronal excitability is a central feature of fragile X syndrome, but the mechanisms are not fully understood. This study shows that pyramidal cells in the entorhinal cortex of Fmr1 knockout mice have a lowered action potential threshold and heightened excitability driven by an increase in persistent sodium current. The abnormal INaP appears to be mediated by enhanced signaling in the mGluR5–PLC–PKC pathway. These results identify dysregulation of sodium channels as a key contributor to cortical hyperexcitability in fragile X, and they reveal a mechanism linking aberrant mGluR5 signaling to increased neuronal firing in this mouse model.
“Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout mice” by Pan-Yue Deng and Vitaly A. Klyachko, Cell Reports. Published online September 20, 2016. doi:10.1016/j.celrep.2016.08.046