Enhanced Long-Term Synaptic Depression in an Animal Model of Depression

Department of Psychiatry, University of Freiburg, Freiburg, Germany.
Biological Psychiatry (Impact Factor: 10.26). 08/2007; 62(1):92-100. DOI: 10.1016/j.biopsych.2006.07.007
Source: PubMed


A growing body of evidence suggests a disturbance of brain plasticity in major depression. In contrast to hippocampal neurogenesis, much less is known about the role of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) regulate the strength of synaptic transmission and the formation of new synapses in many neural networks. Therefore, we examined the modulation of synaptic plasticity in the chronic mild stress animal model of depression.
Adult rats were exposed to mild and unpredictable stressors for 3 weeks. Thereafter, long-term synaptic plasticity was examined in the hippocampal CA1 region by whole-cell patch clamp measurements in brain slices. Neurogenesis was assessed by doublecortin immunostaining.
Exposure to chronic mild stress facilitated LTD and had no effect on LTP. Chronic application of the antidepressant fluvoxamine during the stress protocol prevented the facilitation of LTD and increased the extent of LTP induction. Neurogenesis in the dentate gyrus was impaired after chronic stress.
In addition to neurogenesis, long-term synaptic plasticity is an important and ubiquitous form of brain plasticity that is disturbed in an animal model of depression. Facilitated depression of synaptic transmission might impair function and structure of brain circuits involved in the pathophysiology of major depression. Antidepressants might counteract these alterations.

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Available from: Claus Normann, Jul 15, 2015
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    • "Repeated application of SSRI can enhance LTP (Kojic et al, 1997; Mori et al, 2001). In addition, chronic application of the SSRI fluvoxamine prevented stress-induced facilitation of LTD and increased LTP both in stressed and non-stressed animals (Holderbach et al, 2007). Activation of 5-HT receptors was also shown to block LTD or further convert LTD induction into LTP (Kemp and Manahan-Vaughan, 2005; Normann and Clark, 2005). "
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    ABSTRACT: Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared to single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via NMDA receptor antagonism. 12 healthy subjects received placebo medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took citalopram (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (citalopram and placebo medication with anodal/ cathodal tDCS, citalopram and dextromethorphan (150 mg) with anodal/ cathodal tDCS). Plasticity was monitored by motor evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of citalopram increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.Neuropsychopharmacology accepted article preview online, 02 September 2015. doi:10.1038/npp.2015.270.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2015; DOI:10.1038/npp.2015.270 · 7.05 Impact Factor
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    • "Anhedonia, social avoidance, learned helpless behavior on the FST. No change in anxiety behavior Stein-Behrens et al., 1994; Sousa et al., 2000; Lee et al., 2006; Holderbach et al., 2007; Kompagne et al., 2008; Bessa et al., 2009; de Vasconcellos-Bittencourt et al., 2011; Gong et al., 2011; Ma et al., 2011 "
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    ABSTRACT: Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.
    Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.33 Impact Factor
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    • "Impaired synaptic plasticity has been hypothesized to correlate with both cognitive deficits and the emotional symptoms of depression (Castren, 2013), and impaired hippocampal LTP has been shown in several models of depression (Holderbach et al., 2007; Gómez-Galán et al., 2013). In addition, the FSL rats display an increased spontaneous glutamate transmission due to reduced levels of the astrocytic glutamate transporter GLAST (Gómez-Galán et al., 2013). "
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    ABSTRACT: Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission.
    The International Journal of Neuropsychopharmacology 03/2015; DOI:10.1093/ijnp/pyv032 · 4.01 Impact Factor
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