期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：7
DOI：10.1073/pnas.2022726119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Dravet syndrome (DS) is a severe childhood epileptic encephalopathy characterized by intractable seizures and comorbidities, including a high rate of premature mortality. DS is mainly caused by loss-of-function mutations of the
Scn1a gene encoding sodium channel Na
v1.1 that is predominantly expressed in inhibitory parvalbumin-containing (PV) interneurons. Decreased Na
v1.1 impairs PV cell function, causing DS phenotypes. Effective pharmacological therapy targeting defective PV interneurons is currently not available. This study demonstrated that early treatment with a partial TrkB receptor agonist, LM22A-4, increased Na
v1.1 expression, improved PV interneuron function, and reduced seizure occurrence and mortality rate in DS mice, suggesting a potential therapy for DS.
Dravet syndrome (DS) is one of the most severe childhood epilepsies, characterized by intractable seizures and comorbidities including cognitive and social dysfunction and high premature mortality. DS is mainly caused by loss-of-function mutations in the
Scn1a gene encoding Na
v1.1 that is predominantly expressed in inhibitory parvalbumin-containing (PV) interneurons. Decreased Na
v1.1 impairs PV cell function, contributing to DS phenotypes. Effective pharmacological therapy that targets defective PV interneurons is not available. The known role of brain-derived neurotrophic factor (BDNF) in the development and maintenance of interneurons, together with our previous results showing improved PV interneuronal function and antiepileptogenic effects of a TrkB receptor agonist in a posttraumatic epilepsy model, led to the hypothesis that early treatment with a TrkB receptor agonist might prevent or reduce seizure activity in DS mice. To test this hypothesis, we treated DS mice with LM22A-4 (LM), a partial agonist at the BDNF TrkB receptor, for 7 d starting at postnatal day 13 (P13), before the onset of spontaneous seizures. Results from immunohistochemistry, Western blot, whole-cell patch-clamp recording, and in vivo seizure monitoring showed that LM treatment increased the number of perisomatic PV interneuronal synapses around cortical pyramidal cells in layer V, upregulated Na
v1.1 in PV neurons, increased inhibitory synaptic transmission, and decreased seizures and the mortality rate in DS mice. The results suggest that early treatment with a partial TrkB receptor agonist may be a promising therapeutic approach to enhance PV interneuron function and reduce epileptogenesis and premature death in DS.
