A possible new pathway for treating epileptic seizures in patients with
autism

Date:
September 14, 2021
Source:
Purdue University
Summary:
Researchers have discovered that in Nav1.2 deficient neurons,
the expressions of many potassium channels are surprisingly
reduced. The Nav1.2 deficiency itself doesn't cause seizures; the
issue arises when the potassium channels over-compensate for the
sodium channels' deficiency by shutting down too many potassium
channels, making the neuron hyperexcitable, which causes seizures.



FULL STORY ========================================================================== Autism affects about 2% of children in the United States, and about 30%
of these children have seizures. Recent large-scale genetic studies
revealed that genetic variants in a sodium channel, called voltage-gated
sodium channel Nav1.2, is a leading cause of autism. Overactive sodium
channels in the neuron cause seizures. Doctors often treat seizures
by giving the patient a medication meant to close the sodium channels,
reducing the flow of sodium through axons.

For many patients such treatment works, but in some cases -- up to 20 or
30% - - the treatment doesn't work. These children have "loss-of-function" variants in Nav1.2, which is expected to reduce the sodium channel
activity as "anti- seizures." Thus, how the deficiency in sodium channel
Nav1.2 leads to seizures is a major mystery in the field that puzzles physicians and scientists.


==========================================================================
Yang Yang, an assistant professor of medicinal chemistry and molecular pharmacology at Purdue University, and his team, including first-author
of the paper post-doctoral researcher Jingliang Zhang, tackled the
issue. They discovered that in Nav1.2 deficient neurons, the expressions
of many potassium channels are surprisingly reduced. The Nav1.2 deficiency itself doesn't cause seizures; the issue arises when the potassium
channels over-compensate for the sodium channels' deficiency by shutting
down too many potassium channels, making the neuron hyperexcitable, which causes seizures. In such cases, treating the sodium channel clearly does
not work. Yang and his team suggest that developing medicines to open the potassium channels would help control seizures in these patients. Notably, researchers from the University of California, San Francisco led by Kevin Bender's research group made a similar observation independently. Yang
and Bender's papers were published back-to-back in the same issue of
Cell Reports.

"We're looking at genetic makeup, so doctors can proscribe a drug and
gene therapy based on genes identified -- personalized medicines," Yang
said. "Our research points toward a direction for future research, maybe
future treatments. We are peacetime warriors, fighting humanity's biggest enemy: disease. There are kids dying because of these conditions. Our
goal is to help them, to help their parents and their families. This kind
of basic research is a vital part of finding new drugs." Funding This
work is supported by the Showalter Research Trust and the Purdue Big
Idea Challenge 2.0 on Autism (to Y.Y.). The research reported in this publication was also supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS117585
and R01NS123154 to Y.Y.). The authors gratefully acknowledge support
from the FamilieSCN2A Foundation for Action Potential Grant support, and
Purdue Institute for Drug Discovery and Purdue Institute for Integrative Neuroscience for additional funding support. This project was supported
in part by the Indiana Spinal Cord and Brain Injury Research Fund and
the Indiana CTSI, funded in part by UL1TR002529 from the NIH. The Yang
lab appreciates bioinformatics support from the Collaborative Core for
Cancer Bioinformatics (C3B) of the IU Simon Comprehensive Cancer Center (P30CA082709), PCCR (P30CA023168) and the Walther Cancer Foundation.

========================================================================== Story Source: Materials provided by Purdue_University. Original written
by Brittany Steff.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jingliang Zhang, Xiaoling Chen, Muriel Eaton, Jiaxiang Wu,
Zhixiong Ma,
Shirong Lai, Anthony Park, Talha S. Ahmad, Zhefu Que, Ji Hea Lee,
Tiange Xiao, Yuansong Li, Yujia Wang, Maria I. Olivero-Acosta,
James A. Schaber, Krishna Jayant, Chongli Yuan, Zhuo Huang, Nadia
A. Lanman, William C.

Skarnes, Yang Yang. Severe deficiency of the voltage-gated sodium
channel NaV1.2 elevates neuronal excitability in adult mice. Cell
Reports, 2021; 36 (5): 109495 DOI: 10.1016/j.celrep.2021.109495 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210914184744.htm

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