Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.

Brain Derived Neurotrophic Factor (BDNF) is a potent modulator of brain synaptic plasticity. Signaling defects caused by dysregulation of its NTrk2 (TrkB) kinase (TrkB.FL) and truncated receptors (TrkB.T1) have been linked to the pathophysiology of several neurological and neurodegenerative disorders. We found that upregulation of Rbfox1, an RNA binding protein associated with intellectual disability, epilepsy and autism, increases selectively hippocampal TrkB.T1 isoform expression. Physiologically, increased Rbfox1 impairs BDNF-dependent LTP which can be rescued by genetically restoring TrkB.T1 levels. RNA-seq analysis of hippocampi with upregulation of Rbfox1 in conjunction with the specific increase of TrkB.T1 isoform expression also shows that the genes affected by Rbfox1 gain of function are surprisingly different from those influenced by Rbfox1 deletion. These findings not only identify TrkB as a major target of Rbfox1 pathophysiology but also suggest that gain or loss of function of Rbfox1 regulate different genetic landscapes. Hippocampi of 3 control mice (N-cre) and 3 Rbfox1 overexpressing mice (N-cre;Fox1) were used for RNA-seq isoform-expression analysis.脑源性神经营养因子（Brain Derived Neurotrophic Factor, BDNF）是一种强效的大脑突触可塑性调节剂。其受体NTrk2（TrkB）全长激酶（TrkB.FL）与截短型受体（TrkB.T1）的调控异常所引发的信号传导缺陷，已与多种神经及神经退行性疾病的病理生理学机制相关联。我们发现，与智力障碍、癫痫及孤独症相关的RNA结合蛋白（RNA binding protein）Rbfox1的上调，会选择性地升高海马体中TrkB.T1亚型的表达。生理层面上，Rbfox1水平升高会损害脑源性神经营养因子依赖的长时程增强（long-term potentiation, LTP）效应，而通过遗传学手段恢复TrkB.T1的表达水平可逆转这一损伤。对Rbfox1上调且TrkB.T1亚型特异性升高的海马体进行RNA测序（RNA-seq）分析的结果显示，Rbfox1功能获得所影响的基因，与Rbfox1功能缺失所调控的基因存在显著差异，这一现象出人意料。这些发现不仅确定TrkB是Rbfox1病理生理学机制的关键靶点，同时提示Rbfox1的功能获得与功能缺失会调控不同的基因表达谱。本研究共使用3只对照小鼠（N-cre）与3只Rbfox1过表达小鼠（N-cre;Fox1）的海马组织，进行RNA测序亚型表达分析。