The guanine nucleotide exchange factor RapGEF2 is required for ERK-dependent immediate-early gene (Egr1) activation during fear memory formation.

Autor: Jiang SZ; Section On Molecular Neuroscience, NIMH Intramural Research Program, 9000 Rockville Pike, Building 49, Room 5A38, Bethesda, MD, 20892, USA., Shahoha M; 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., Zhang HY; Section On Molecular Neuroscience, NIMH Intramural Research Program, 9000 Rockville Pike, Building 49, Room 5A38, Bethesda, MD, 20892, USA., Brancaleone W; Section On Molecular Neuroscience, NIMH Intramural Research Program, 9000 Rockville Pike, Building 49, Room 5A38, Bethesda, MD, 20892, USA., Elkahloun A; Microarray Core, NHGRI-IRP, Bethesda, MD, USA., Tejeda HA; Unit on Neuromodulation and Synaptic Integration, NIMH-IRP, Bethesda, MD, USA., Ashery U; 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. uriashery@gmail.com., Eiden LE; Section On Molecular Neuroscience, NIMH Intramural Research Program, 9000 Rockville Pike, Building 49, Room 5A38, Bethesda, MD, 20892, USA. eidenl@mail.nih.gov.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Jan 18; Vol. 81 (1), pp. 48. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1007/s00018-023-04999-y
Abstrakt: 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 fl/fl 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 fl/fl 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 fl/fl 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 fl/fl 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.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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