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Neuronal and synaptic plasticity in subregions of rat hippocampus after antidepressant treatment

Fenghua Chen  


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Accepted by: Health Sciences Aarhus University
Defended on: February 22, 2009
Official opponents: Karsten Nielsen, Chief Consultant, MD, DrMSc , Andreas Reif, Professor, MD, PhD , Connie Sanchez, Vice President, MD, DrmedSc
Tutors: Jens Randel Nyengaard, Professor, MD, DrMSc , Torsten Meldgaard Madsen, Head of Department, MD, PhD , Gregers Wegener, Chief Consultant, MD, PhD

Published in the PhD Database: February 24, 2009


English abstract
Neuronal plasticity in the hippocampal formation is thought to play an important role in the pathophysiology of depression and effects of antidepressant therapy. Depression may result from an impairment of neurons in the hippocampus which makes it impossible to make appropriate adaptations and / or synaptic connections. Chronic antidepressant therapy increases levels of neurotrophic factors, cell proliferation and neurogenesis; it possibly stimulates outgrowth and regeneration of dendrites and axons, as well as promoting synaptogenesis in the hippocampus. Therefore, these neuroplastic events may ultimately be the underlying mechanism of antidepressant drug action.

The PhD thesis includes three projects, which are aimed at investigating the underlying effect of antidepressants (imipramine in study I and III and repeated seizures in study II) on the neuronal plasticity in subregions of the hippocampus in normal rats (study I and II) and in an animal model of depression (study III). Design-based stereological methods were used to quantify regional volumes and the number of neurons and synapses.
In study I, we found that the number and percentage of spine synapses increased significantly and, conversely, the percentage of asymmetric shaft synapses significantly decreased following 14 days of imipramine treatment.
In study II, the results showed that volumes of Dentate Gyrus (DG) and Hilus of the hippocampus were significantly larger in the ECS treatment group. The neuron number in DG, synapse number (including total synapses, spine synapses, and both perforated and nonperforated spine synapse subtypes) in CA1 were significantly increased in the ECS treatment group.
In study III, we found that regional volume, neuron number, and synapse number (including nonperforated and perforated spine synapses) were significantly smaller in the FSL rats, and were related to decreased immobility in the forced swim test. The neuron numbers in the DG was significantly increased in the imipramine treated FSL rats, furthermore, the neuron numbers in the DG and Hilus showed no differences in the treated FSL rats compared with the FRL rats. The spine synapse (including nonperforated and perforated spine synapses) numbers increased significantly following imipramine treatment and, conversely, the shaft synapse numbers significantly decreased in the imipramine treated FSL rats.
Our findings provide experimental evidence for supporting the recent theories that major depression may be related to impairments of structural plasticity and neural cellular resilience, and that antidepressants counteract the structural impairments.



Danish abstract
Nyere hypoteser tyder på, at svære depressioner kan være relateret til nedsættelse af strukturel plasticitet og neurale cellers modstandsdygtighed, og at antidepressiva kan modvirke dette. Den neuronale plasticitet i hippocampus spiller en vigtig rolle i patofysiologien af depression og effekten af antidepressiv behandling. Depression kan skyldes en forstyrrelse af neuroner i hippocampus, der har nedsat evne til at foretage tilpasninger og/eller lave synaptiske forbindelser. Kronisk antidepressiv behandling øger niveauet af neurotrofiske faktorer, celledeling og neurogenese, og stimulerer muligvis udvækst og revitalisering af dendritter og axoner, samt fremmer synaptogenesen i hippocampus. Derfor kan disse neuroplastiske begivenheder i sidste ende være den underliggende mekanisme i antidepressiv behandling.

Ph.d.-afhandlingen omfatter tre projekter, som undersøger de underliggende virkninger af antidepressiv behandling (imipramin i studie I og III og ECS ¿ ¿Electro Convulsive Seizure¿ - i studie II) på neuronal plasticitet i subregioner af hippocampus i normale rotter (studie I og II) og en dyremodel af depression (studie III). Design-baserede stereologiske metoder blev anvendt til at kvantificere de regionale volumina samt antal neuroner og synapser.

I studie I var antal og procentdel af ¿spine¿ synapser steget signifikant, og omvendt, en procentdel af asymmetriske ¿shaft¿ synapser var signifikant mindre efter 14 dages imipramin behandling.

I studie II, viste resultaterne, at volumen af Gyrus Dentatus (DG) og Hilus af hippocampus var signifikant større i ECS behandlings gruppen. Neuron antal i DG og synapse antal (herunder samlet antal synapser, ¿spine¿ synapser, perforerede og ikkeperforerede ¿spine¿ synapse undertyper) i CA1 blev signifikant forøget i ECS behandlingsgruppen.

I studie III, opdagede vi, at det regionale volumen, neuron antal og synapse antal (herunder ikkeperforerede og perforerede ¿spine¿ synapser) var signifikant mindre i Flinder Sensitive Line (FSL) rotter og det korrelerede til ubevægeligheden i tvunget svømmetest. Neuron antallet i DG blev signifikant forøget i imipramin behandlet FSL rotter. Neuron antallet i DG og Hilus viste ingen forskelle i de behandlede FSL rotter sammenlignet med Flinder Resistant Line (FRL) rotter. Antal ¿spine¿ synapser (herunder ikkeperforerede og perforerede ¿spine¿ synapser) steg signifikant efter imipramin behandling, og omvendt, antal ¿shaft¿ synapser faldt signifikant efter imipramin behandling i FSL rotter.

Vores resultater giver eksperimentel støtte til de seneste teorier, om at forringelse af neuronal levedygtighed og neuroplasticitet kan være vigtige årsagsfaktorer i depressive lidelser, og at antidepressiv behandling er en potentiel stimulator af neural cellulær modstandskraft i hippocampus og kan reducere de strukturelle mangler. Det er dog vigtigt at huske at resultaterne er begrænset til dyreforsøg. Den kliniske værdi af disse resultater er vanskelig at vurdere selv i store multi-center kliniske undersøgelser.