Major Depressive Disorder (MDD) is characterized by smaller hippocampus and fewer granule neurons (GNs). In contrast, MDD subjects treated with selective serotonin reuptake inhibitors (MDD*SSRI) have control levels of GNs and neuronal progenitor cells (NPCs) and normal dentate gyrus (DG) volume. We hypothesize a deficit of maturation and survival of DG cells in MDD, reversed by SSRI, possibly through action on intracellular cascades regulated by serotonin receptors (HTRs). The ventral DG regulates emotional processing, it has higher serotonergic projections than the dorsal DG in humans and mice. HTR1A mRNA density in anterior DG correlates in humans with mitotic and mature GN number and is necessary for SSRI action on neurogenesis in mice. We hypothesize: (1) NPCs, mitotic cells, immature neuroblasts, mature GNs and neuroblast dendrite arborization in human anterior DG correlate with HTR2A and HTR4 mRNA density; (2) GNs, neuroblasts and neuroblast dendrite arborization correlate with cells expressing molecules promoting proliferation (mTOR), cell maturation/dendritic development (CREB), cell survival (BCL2), DNA repair and synaptic plasticity (PARP), and inversely correlate with molecules preventing cell cycle progression, migration, and survival (PTEN) or promoting cell death via apoptosis or inflammation (Caspase3); (3) The effects of SSRIs on neurogenesis and behavior are altered in mice with ventral hippocampus-specific deletions of HTR1A, HTR4 and HTR2A; (4) The effects of HTRs on GN activity are sufficient to increase neurogenesis and produce antidepressant-like effects in mice. Our approach combines human and mouse studies to test mechanisms of HRTs action on intracellular molecules controlling maturation and survival. In matched untreated MDD, MDD*SSRI, and controls, we will determine HTR1A, HTR2A, and HTR4 mRNA (nCi /mg) density and will correlate that with number of NPCs, immature neuroblasts, mature GNs and neuroblast dendrite length in the DG. We will assess numbers of cells expressing markers promoting (mTOR, CREB, BCL2, PARP) or preventing (PARP, Caspase3) cell maturation and/or survival. We will correlate their expression with mature GN and neuroblast number, dendrite length and HTR mRNA densities in human and in a mice depression model. We generated mice lacking HTR1A or HTR4 in whole or just ventral DG, mice lacking HTR2A from hilar mossy cells and ventral CA3, as well as mice expressing inhibitory and excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) in GNs or mossy cells, which mimic HTR1A (inhibitory), HTR4 and HTR2A (excitatory). In wild type, HTR Kos and DREADD mice, we will quantify mitotic cells, NPCs, neuroblasts, GNs, neuroblast dendrite length, intracellular cascades studied in human, behavioral responses to chronic unpredictable stress and chronic treatment with fluoxetine. Results should inform the pathogenesis of depression and lead to new therapies that target relevant HTRs or downstream effectors.

Public Health Relevance

Major Depressive Disorder (MDD), one of the leading causes of global disease burden, is characterized by deficits in the anterior dentate gyrus (DG) of the hippocampus including reduced volume, granule neuron (GN) number and serotonin receptor (HTR) mRNA density. Conversely, serotonin reuptake inhibitor (SSRI), enhance DG proliferation, maturation, and survival, but the mechanism of their action is unknown. We propose to elucidate this question with a unique approach combining human postmortem studies in well-characterized MDD, SSRI-treated MDD and controls, and studies in mice that are tissue-specific HTR knockouts or express engineered receptors, to test the hypothesis that SSRIs act, via HTRs, on intracellular cascades controlling hippocampal neuroplasticity, ultimately affecting behavioral responses to stress and antidepressant treatment.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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New York State Psychiatric Institute
New York
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Thom, M; Boldrini, M; Bundock, E et al. (2018) Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking. Neuropathol Appl Neurobiol 44:32-55
Pillai, Rajapillai L I; Zhang, Mengru; Yang, Jie et al. (2018) Will imaging individual raphe nuclei in males with major depressive disorder enhance diagnostic sensitivity and specificity? Depress Anxiety 35:411-420
Boldrini, Maura; Fulmore, Camille A; Tartt, Alexandria N et al. (2018) Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell 22:589-599.e5
Anacker, Christoph; Luna, Victor M; Stevens, Gregory S et al. (2018) Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 559:98-102
Nautiyal, Katherine M; Hen, René (2017) Serotonin receptors in depression: from A to B. F1000Res 6:123
Anacker, Christoph; Hen, René (2017) Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci 18:335-346
Azmitia, E C; Saccomano, Z T; Alzoobaee, M F et al. (2016) Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum. J Autism Dev Disord 46:1307-18
Donaldson, Z R; le Francois, B; Santos, T L et al. (2016) The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription. Transl Psychiatry 6:e746
Samuels, Benjamin Adam; Mendez-David, Indira; Faye, Charlène et al. (2016) Serotonin 1A and Serotonin 4 Receptors: Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants. Neuroscientist 22:26-45
Nautiyal, Katherine M; Tritschler, Laurent; Ahmari, Susanne E et al. (2016) A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors. Neuropsychopharmacology 41:2941-2950

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