Neurophysiological mechanisms of plasticity induced in adult brain

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http://urn.fi/URN:ISBN:978-951-51-1840-0
Title: Neurophysiological mechanisms of plasticity induced in adult brain
Author: Popova , Dina
Contributor: University of Helsinki, Faculty of Veterinary Medicine
Neuroscience center, Helsinki University
Thesis level: Doctoral dissertation (article-based)
Abstract: Dynamic modifications of synaptic connectivity enables the brain to adequately respond to environmental challenges. This ability, known as synaptic plasticity, peaks during the early postnatal period, yet it is maintained throughout life. Interestingly, antidepressants (ADs) and AD-like drugs can promote neuronal plasticity in the adult brain, a phenomenon recently suggested to contribute to the mood-improving effects of ADs. However, the mechanisms underlying AD-induced neuronal network refinement are still poorly understood. The main goal of this thesis was to advance our understanding of the mechanisms associated with pharmacologically-enhanced plasticity in the adult brain. Two pharmacologically distinct compounds with AD-like actions, namely the selective serotonin reuptake inhibitor fluoxetine (Flx) and the volatile anesthetic isoflurane were used to enhance synaptic plasticity in the rodent cortex and hippocampus. After drug exposure, behavioral, molecular, histological and in vitro electrophysiological approaches were utilized to investigate the effects of Flx and ISO on synaptic function and plasticity. Using electrophysiological recordings in brain slices, we show that chronic Flx treatment results in increased short- and long-term plasticity as well as enhanced basal transmission in excitatory CA3-CA1 synapses in the hippocampus. These changes were paralleled by an activity-dependent enhancement in the expression of proteins related to vesicular trafficking and release, such as synaptophysin, synaptotagmin 1, mammalian uncoordinated protein 18 (Munc 18) and syntaxin 1. Moreover, Flx treatment reduced the percentage of parvalbumin-expressing GABAergic neurons, increased the expression of polysialylated-neural cell adhesion molecule (PSA-NCAM) and decreased the expression of the potassium-chloride co-transporter 2 (KCC2) in the basolateral amygdala and in the medial prefrontal cortex (mPFC). All the above findings are likely to be attributed to increased dynamic range of synaptic plasticity induced by Flx. Our behavioral findings demonstrate that long term Flx administration in combination with extinction training results in long-term loss of fearful memories while the Flx treatment alone failed to influence fear behavior. These data suggest that behavioral training is indispensable for the guidance of Flx-induced network plasticity. Exposure to isoflurane promotes long-term synaptic plasticity and enhances basal synaptic transmission in excitatory CA3-CA1 synapses in the mouse hippocampus. These changes were correlated with increased tropomyosin receptor kinase B (TrkB) signaling through the mammalian target of rapamycin (mTOR) pathway in the prefrontal cortex and hippocampus and led to rapid antidepressant-like behavioral effects in the forced swim test. Taken together, our findings highlight that Flx and isoflurane enhance synaptic plasticity in hippocampal and cortical excitatory synapses, however, the underlying molecular mechanisms as well as behavior improvements were different. In conclusion, the results described in this work provide a mechanistic background for adult brain plasticity and network tuning, with high practical significance to the design of clinical therapy.
URI: URN:ISBN:978-951-51-1840-0
http://hdl.handle.net/10138/158776
Date: 2015-12-18
Subject: neuroscience
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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