Jiang Sunny Zhihong, Shahoha Meishar, Zhang Hai-Ying, Brancaleone William, Elkahloun Abdel, Tejeda Hugo A, Ashery Uri, Eiden Lee E
Section On Molecular Neuroscience, NIMH Intramural Research Program, 9000 Rockville Pike, Building 49, Room 5A38, Bethesda, MD, 20892, USA.
School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, and Sagol School of Neuroscience, Tel Aviv University, Sherman Building Rm 719, Ramat Aviv, 69978, Tel Aviv, Israel.
Cell Mol Life Sci. 2024 Jan 18;81(1):48. doi: 10.1007/s00018-023-04999-y.
The MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for neuronal ERK activation are undetermined. RapGEF2 is a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether it is required for cAMP-dependent ERK activation leading to other downstream neuronal signaling events occurring during associative learning, and if RapGEF2-dependent signaling impairments affect learned behavior. Camk2α-cre::RapGEF2 mice with depletion of RapGEF2 in hippocampus and amygdala exhibit impairments in context- and cue-dependent fear conditioning linked to corresponding impairment in Egr1 induction in these two brain regions. Camk2α-cre::RapGEF2 mice show decreased RapGEF2 expression in CA1 and dentate gyrus associated with abolition of pERK and Egr1, but not of c-Fos induction, following fear conditioning, impaired freezing to context after fear conditioning, and impaired cAMP-dependent long-term potentiation at perforant pathway and Schaffer collateral synapses in hippocampal slices ex vivo. RapGEF2 expression is largely eliminated in basolateral amygdala, also involved in fear memory, in Camk2α-cre::RapGEF2 mice. Neither Egr1 nor c-fos induction in BLA after fear conditioning, nor cue-dependent fear learning, are affected by ablation of RapGEF2 in BLA. However, Egr1 induction (but not that of c-fos) in BLA is reduced after restraint stress-augmented fear conditioning, as is freezing to cue after restraint stress-augmented fear conditioning, in Camk2α-cre::RapGEF2 mice. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. Here we show a functional link between one of them, RapGEF2, and cognitive processes involved in associative learning in amygdala and hippocampus.
丝裂原活化蛋白激酶细胞外信号调节激酶（MAP kinase ERK）对于联想学习背后的神经元可塑性很重要，然而神经元ERK激活的特定分子途径尚未确定。RapGEF2是一种神经元特异性的环磷酸腺苷（cAMP）传感器，可介导ERK激活。我们研究了它是否是cAMP依赖性ERK激活所必需的，这种激活会导致联想学习过程中发生的其他下游神经元信号事件，以及RapGEF2依赖性信号损伤是否会影响学习行为。海马体和杏仁核中RapGEF2缺失的Camk2α-cre::RapGEF2小鼠在情境和线索依赖性恐惧条件反射中表现出损伤，这与这两个脑区中早期生长反应蛋白1（Egr1）诱导的相应损伤有关。Camk2α-cre::RapGEF2小鼠在恐惧条件反射后，CA1和齿状回中RapGEF2表达降低，同时pERK和Egr1的诱导消失，但c-Fos的诱导未受影响，恐惧条件反射后对情境的僵立反应受损，并且在体外海马切片中穿通通路和海马苔状纤维侧支突触处的cAMP依赖性长时程增强受损。在Camk2α-cre::RapGEF2小鼠中，同样参与恐惧记忆的基底外侧杏仁核中的RapGEF2表达也基本消除。恐惧条件反射后，基底外侧杏仁核中Egr1和c-fos的诱导以及线索依赖性恐惧学习均不受基底外侧杏仁核中RapGEF2缺失的影响。然而，在束缚应激增强的恐惧条件反射后，Camk2α-cre::RapGEF2小鼠基底外侧杏仁核中Egr1的诱导（但不是c-fos的诱导）减少，束缚应激增强的恐惧条件反射后对线索的僵立反应也减少。环磷酸腺苷依赖性鸟苷酸交换因子（GEFs）在基因上已被确定为精神分裂症的危险因素，精神分裂症是一种与认知缺陷相关的疾病。在这里，我们展示了其中之一RapGEF2与杏仁核和海马体中联想学习所涉及的认知过程之间的功能联系。
