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Perinatal interference with the serotonergic system affects VTA function in the adult via glutamate co-transmission

Abstract

Serotonin and dopamine are associated with multiple psychiatric disorders. How they interact during development to affect subsequent behavior remains unknown. Knockout of the serotonin transporter or postnatal blockade with selective serotonin reuptake inhibitors (SSRIs) leads to novelty-induced exploration deficits in adulthood, potentially involving the dopamine system. Here, we show in the mouse that raphe nucleus serotonin neurons activate ventral tegmental area dopamine neurons via glutamate co-transmission and that this co-transmission is reduced in animals exposed postnatally to SSRIs. Blocking serotonin neuron glutamate co-transmission mimics this SSRI-induced hypolocomotion, while optogenetic activation of dopamine neurons reverses this hypolocomotor phenotype. Our data demonstrate that serotonin neurons modulate dopamine neuron activity via glutamate co-transmission and that this pathway is developmentally malleable, with high serotonin levels during early life reducing co-transmission, revealing the basis for the reduced novelty-induced exploration in adulthood due to postnatal SSRI exposure.

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Fig. 1: Serotonin—VGLUT3 colocalization.
Fig. 2: Optogenetic stimulation of serotonergic terminals activates dopaminergic cells via glutamate.
Fig. 3: Optogenetic activation of serotonergic cells elicits place-preference and hyperlocomotion by activating the VTA.
Fig. 4: Postnatal-fluoxetine exposure led to deficits in glutamatergic transmission.
Fig. 5: Postnatal-fluoxetine exposure led to deficits in exploration that were mimicked by ablation of VGLUT3 in Pet1+ cells.
Fig. 6: Stimulation of serotonergic terminals in the VTA did not fully rescue the hypolocomotor phenotype of fluoxetine-treated mice. Stimulation of dopaminergic cells did.

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Acknowledgements

This work has been supported by the National Institute of Child Health and Human Development (R01 HD095966 and R03 HD094978, CMT) and the National Institute on Drug Abuse (R01 DA038966, SR).

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CMT and MSA designed the experiments. CMT, CC, JFS, NC, CB, ECM and RS performed the experiments and analyzed the data. RPS, RHE and SR contributed new reagents or analytic tools. CMT, CC, JFS, NC, MSA and FXC wrote the paper with contributions from all co-authors.

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Correspondence to Catia M. Teixeira.

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Cunha, C., Smiley, J.F., Chuhma, N. et al. Perinatal interference with the serotonergic system affects VTA function in the adult via glutamate co-transmission. Mol Psychiatry 26, 4795–4812 (2021). https://doi.org/10.1038/s41380-020-0763-z

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