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Pet-1 is required across different stages of life to regulate serotonergic function

Nature Neuroscience volume 13, pages 1190–1198 (2010)Cite this article

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Abstract

Transcriptional cascades are required for the specification of serotonin (5-HT) neurons and behaviors modulated by 5-HT. Several cascade factors are expressed throughout the lifespan, which suggests that their control of behavior might not be temporally restricted to programming normal numbers of 5-HT neurons. We used new mouse conditional targeting approaches to investigate the ongoing requirements for Pet-1 (also called Fev), a cascade factor that is required for the initiation of 5-HT synthesis, but whose expression persists into adulthood. We found that Pet-1 was required after the generation of 5-HT neurons for multiple steps in 5-HT neuron maturation, including axonal innervation of the somatosensory cortex, expression of appropriate firing properties, and the expression of the Htr1a and Htr1b autoreceptors. Pet-1 was still required in adult 5-HT neurons to preserve normal anxiety-related behaviors through direct autoregulated control of serotonergic gene expression. These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription.

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Figure 1: Conditional deletion of Pet-1 after specification of 5-HT neuronal fate.
Figure 2: Continued Pet-1 function is required for maturation of serotonergic axonal innervation patterns.
Figure 3: Continued Pet-1 function is required for 5-HT neuron firing properties and inhibitory autoreceptor function.
Figure 4: Continued Gata3 expression is needed to maintain 5-HT gene expression but not autoreceptor function.
Figure 5: Stage-specific disruption of Pet-1 in the adult ascending 5-HT system.
Figure 6: Disruption of Pet-1-dependent transcription in the adult ascending 5-HT system causes elevated anxiety-like behavior.
Figure 7: 5-HT synthesis and Slc6a4 expression are maintained in the adult ascending 5-HT system through positively autoregulated direct Pet-1 transactivation.

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Acknowledgements

We thank L. Landmesser for suggestions on retrograde tracing; S. Dymecki and P. Chambon for CreERT2 plasmids; Q. Ma for the mycPet-1 vector; J. Zhu for the Gata3loxP/loxP mice; K. Lobur for assistance with genotyping of mice; J. Reeves for behavioral testing in the Case Rodent Behavior Core; and L. Landmesser, S. Maricich and J. Silver for comments on the manuscript. This work was supported by grants MH062723 and MH078028 to E.S.D. (US National Institutes of Health).

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  1. Takashi Maejima & Stefan Herlitze

    Present address: Present address: Department of General Zoology and Neurobiology, Ruhr University, Bochum, Germany.,

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  1. Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA

    Chen Liu, Takashi Maejima, Steven C Wyler, Gemma Casadesus, Stefan Herlitze & Evan S Deneris

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Contributions

E.S.D. conceived the project. C.L. made the transgenic and targeting constructs, characterized all new mouse lines and generated all histological, RT-PCR and retrograde tracing data and images. C.L. and S.C.W. performed western blot analyses. C.L. and G.C. performed behavioral analyses. T.M. and S.H. generated the electrophysiology data. C.L., S.H., T.M., G.C., S.C.W. and E.S.D. analyzed the data. E.S.D. and C.L. designed the experiments and wrote the manuscript.

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Correspondence to Evan S Deneris.

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Liu, C., Maejima, T., Wyler, S. et al. Pet-1 is required across different stages of life to regulate serotonergic function. Nat Neurosci 13, 1190–1198 (2010). https://doi.org/10.1038/nn.2623

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