Abstract
Synaptic activity-dependent gene expression is critical for certain forms of neuronal plasticity and survival in the mammalian nervous system, yet the mechanisms by which coordinated regulation of activity-induced genes supports neuronal function is unclear. Here, we show that deletion of serum response factor (SRF) in specific neuronal populations in adult mice results in profound deficits in activity-dependent immediate early gene expression, but components of upstream signaling pathways and cyclic AMP–response element binding protein (CREB)-dependent transactivation remain intact. Moreover, SRF-deficient CA1 pyramidal neurons show attenuation of long-term synaptic potentiation, a model for neuronal information storage. Furthermore, in contrast to the massive neurodegeneration seen in adult mice lacking CREB family members, SRF-deficient adult neurons show normal morphologies and basal excitatory synaptic transmission. These findings indicate that the transcriptional events underlying neuronal survival and plasticity are dissociable and that SRF plays a prominent role in use-dependent modification of synaptic strength in the adult brain.
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Acknowledgements
We thank J. Baraban, A. Kolodkin, R. Misra and P. Worley for comments on the manuscript; R. Misra and P. Worley for valuable advice and reagents; the Johns Hopkins Transgenic Core facility for help with generating conditional mice; members of the Ginty, Linden, Kolodkin and Ghosh laboratories for helpful discussions and suggestions and K. Takamiya and R. Huganir for constructs and mice. This study was supported by grants from the US National Institutes of Health to D.J.L. and D.D.G; N.R. is supported by a fellowship from the Damon Runyon Cancer Research Foundation. D.D.G. is an Investigator of the Howard Hughes Medical Institute.
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Supplementary Fig. 1
Extent of SRF depletion in the forebrains of Srff/f;SCre and Srff/f;CKCre mice. (JPG 526 kb)
Supplementary Fig. 2
Normal expression of immediate early genes in CA1 pyramidal neurons in Srff/f;SCre mutants. (a-d)The basal expression of Actb (a,b), Actg1 (c,d) mRNAs as visualized by in situ hybridization (6 week old age- and sex-matched control and Srf f/f;SCre animals, n = 4). The expression of these genes in Srf f/f;SCre mutants is comparable to that seen in Srf f/f control mice. Scale bar, 100 m. (JPG 221 kb)
Supplementary Fig. 3
Decreased basal expression of immediate early genes in CA1 pyramidal neurons. (a–f) The basal expression of Actb (a,b), Actg1 (c,d) and Egr1 (e,f) mRNAs as visualized by in situ hybridization (3 month old age- and sex-matched control and Srf f/f;CKCre mice, n = 4). The Srf f/f;CKCre mutants show decreased expression of these genes as compared to Srf f/f control mice. Scale bar, 100 m. (JPG 153 kb)
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Ramanan, N., Shen, Y., Sarsfield, S. et al. SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability. Nat Neurosci 8, 759–767 (2005). https://doi.org/10.1038/nn1462
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DOI: https://doi.org/10.1038/nn1462
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