Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve ther-apeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here I show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibi-tion of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Fur-thermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. In addition, modulations of mossy cell activity are influence to excitation-inhibition balance in dentate gyrus. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. These results indicate that compounds that target mossy cell activity would be attractive candidates for the development of newer antidepressant medications.
Table Of Contents
Chapter 1. Background 1 1. Major depressive disorder 1 1.1 MDD in the hippocampus 1 2. Antidepressive therapeutics 4
Chapter 2. The role of hippocampal mossy cells in antidepressant actions. 7 1. Introduction 7 1.1 Molecular mechanism of SSRI actions 7 1.2 Mossy cells in the hippocampus 10 1.3 p11, An SSRI-inducible molecule 13 2. Materials and methods 15 2.1 Materials 15 2.1.1 Antibodies 15 2.1.2 Virus strains 15 2.1.3 Recombinant DNAs 16 2.1.4 Chemicals 16 2.1.5 Experimental models 17 2.2 Methods 18 2.2.1 Animal breeding 18 2.2.2 Drug treatment 18 2.2.3 Plasmid constructions 19 2.2.4 Immunoprecipitation of p11/AnxA2/SMARCA3 complex 19 2.2.5 Stereotaxic surgery 20 2.2.6 Behavioral assessments 21 18.104.22.168 Elevated plus maze (EPM) 21 22.214.171.124 Open field test (OF) 22 126.96.36.199 Light and dark box test (LD box) 22 188.8.131.52 Novelty suppressed feeding test (NSF) 22 184.108.40.206 Tail suspension test (TST) 23 2.2.7 Chronic unpredictable mild Stress paradigm 23 2.2.8 Immunohistochemistry 25 2.2.9 BrdU labeling and neurogenesis assay 26 2.2.10 Electrophysiological recordings of mossy cells 27 220.127.116.11 Fluorescence labeling of mossy cells 27 18.104.22.168 Slice preparation 27 22.214.171.124 Electrophysiology 28 2.2.11. Data analysis and statistics 29 3. Results 30 3.1. The role of p11/AnxA2/SMARCA3 complex in hippocampal mossy cells in an-tidepressant responses 30 3.1.1 Effects of genetic deletion of p11 or Smarca3 in hippocampal mossy cells on behavioral responses to chronic SSRI administration 30 3.1.2 Effects of mossy cell-specific inhibition of the p11/AnxA2/SMARCA3 com-plex on neurogenic and behavioral responses to chronic antidepressant treatment 38 3.1.3. Effects of cell type-specific inhibition of the p11/AnxA2/SMARCA3 complex on neuronal activity of mossy cells 50 3.2. The role of hippocampal mossy cells in antidepressant responses 59 3.2.1 Effects of selective stimulation of dentate mossy cells on adult neurogenesis in the hippocampus 59 3.2.2 Effects of selective inhibition of dentate mossy cells on antidepressant actions in the hippocampus 67 3.3. Effects of modulation of mossy cells on micro-circuits in the dentate gyrus 78 4. Discussion 82 Reference 95 Summary in Korean 103