Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

Amin Zahrai,Faranak Vahid-Ansari,Mireille Daigle,Paul R Albert

doi:10.1038/s41398-020-01008-9

Amin Zahrai, Faranak Vahid-Ansari + Show 2 more

Open Access

https://doi.org/10.1038/s41398-020-01008-9

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Journal: Translational Psychiatry	Publication Date: Sep 30, 2020
Citations: 21	License type: open-access

Affiliation: Ottawa Hospital

Abstract

Chronic treatment with fluoxetine (FLX) is required for its antidepressant effects, but the role of serotonin (5-HT) axonal plasticity in FLX action is unknown. To address this, we examined mice with a stroke in the left medial prefrontal cortex (mPFC) resulting in persistent anxiety-like and depression-like behaviors and memory deficits as a model of post-stroke depression. Chronic treatment with FLX (but not exercise) completely reversed the behavioral phenotype and partially reversed changes in FosB-labeled cells in the mPFC, nucleus accumbens, septum, hippocampus, basolateral amygdala (BLA), and dorsal raphe. In these regions, 5-HT or norepinephrine (NE) innervation was quantified by staining for 5-HT or NE transporters, respectively. 5-HT synapses and synaptic triads were identified as synaptophysin-stained sites on 5-HT axons located proximal to gephyrin-stained or PSD95-stained spines. A week after stroke, 5-HT innervation was greatly reduced at the stroke site (left cingulate gyrus (CG) of the mPFC) and the left BLA. Chronically, 5-HT and NE innervation was reduced at the left CG, nucleus accumbens, and BLA, with no changes in other regions. In these areas, pre-synaptic and post-synaptic 5-HT synapses and triads to inhibitory (gephyrin+) sites were reduced, while 5-HT contacts at excitatory (PSD95+) sites were reduced in the CG and prelimbic mPFC. Chronic FLX, but not exercise, reversed these reductions in 5-HT innervation but incompletely restored NE projections. Changes in 5-HT innervation were verified using YFP staining in mice expressing YFP-tagged channelrhodopsin in 5-HT neurons. Thus, FLX-induced 5-HT axonal neuroplasticity of forebrain projections may help mediate recovery from brain injury.

Highlights

Major depression is the most prevalent mental illness[1,2].Post-stroke depression (PSD) occurs within 3 months following stroke and leads to increased mortality and reduced recovery[3,4,5]
5-HT axons spontaneously regrow over a period of months into target tissues[27,29,30]
Using our mouse model of PSD we addressed whether 5-HT axonal regrowth occurs in stroke-damaged tissue and whether antidepressant treatments might enhance this regrowth

Summary

Introduction

Major depression is the most prevalent mental illness[1,2]. Post-stroke depression (PSD) occurs within 3 months following stroke and leads to increased mortality and reduced recovery[3,4,5]. Depression and PSD are treated using first-line antidepressants including selective serotonin (5-HT) reuptake inhibitors (SSRIs)[6,7]. SSRIs augment synaptic 5-HT levels but require several weeks before clinical improvement is seen. This latency may be due to pre-synaptic or post-synaptic adaptations. These adaptations include desensitization of 5-HT1A autoreceptors, enhanced hippocampal neurogenesis, and cortical neuroplasticity[8,9,10].

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Conclusion