Lund Ingrid V, Hu Yinghui, Raol YogendraSinh H, Benham Rebecca S, Faris Ramona, Russek Shelley J, Brooks-Kayal Amy R
Neuroscience Graduate Group and Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Signal. 2008 Oct 14;1(41):ra9. doi: 10.1126/scisignal.1162396.
The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) is the major inhibitory neurotransmitter receptor in the brain. Its multiple subunits show regional, developmental, and disease-related plasticity of expression; however, the regulatory networks controlling GABA(A)R subunit expression remain poorly understood. We report that the seizure-induced decrease in GABA(A)R alpha1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF). BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. JAK/STAT pathway inhibition prevents the seizure-induced decrease in GABA(A)R alpha1 abundance in vivo and, given that BDNF is known to increase the abundance of GABA(A)R alpha4 in a JAK/STAT-independent manner, indicates that BDNF acts through at least two distinct pathways to influence GABA(A)R-dependent synaptic inhibition.
γ-氨基丁酸（GABA）A型受体（GABA(A)R）是大脑中主要的抑制性神经递质受体。其多个亚基在表达上呈现出区域、发育和疾病相关的可塑性；然而，控制GABA(A)R亚基表达的调控网络仍知之甚少。我们报告，癫痫发作诱导的与癫痫相关的GABA(A)R α1亚基表达下降是由脑源性神经营养因子（BDNF）调节的Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径介导的。BDNF和癫痫发作依赖的STAT3磷酸化导致腺苷3',5'-单磷酸（cAMP）反应元件结合蛋白（CREB）家族成员ICER（诱导型cAMP早期阻遏物）在Gabra1:CRE位点与磷酸化的CREB结合。JAK/STAT途径抑制可防止癫痫发作诱导的体内GABA(A)R α1丰度下降，并且鉴于已知BDNF以JAK/STAT非依赖的方式增加GABA(A)R α4的丰度，这表明BDNF通过至少两条不同途径影响GABA(A)R依赖性突触抑制。
