Serotonin Signaling through Prefrontal Cortex 5-HT1A Receptors during Adolescence Can Determine Baseline Mood-Related Behaviors
Alvaro L. Garcia-Garcia,
Qingyuan Meng,
Sarah Canetta,
Alain M. Gardier,
Bruno P. Guiard,
Christoph Kellendonk,
Alex Dranovsky,
E. David Leonardo
Affiliations
Alvaro L. Garcia-Garcia
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA
Qingyuan Meng
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA
Sarah Canetta
Department of Psychiatry, Columbia University, New York, NY 10032, USA
Alain M. Gardier
CESP, University Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry 91290, France
Bruno P. Guiard
CESP, University Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry 91290, France
Christoph Kellendonk
Department of Psychiatry, Columbia University, New York, NY 10032, USA
Alex Dranovsky
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA
E. David Leonardo
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA
Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT1A receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT1A receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT1A heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.
