Dysfunctional Glutamatergic and γ-Aminobutyric Acidergic Activities in Prefrontal Cortex of Mice in Social Defeat Model of Depression

Veeraiah, Pandichelvam; Noronha, Judith Miriam; Maitra, Swati; Bagga, Puneet; Khandelwal, Nitin; Chakravarty, Sumana; Kumar, Arvind; Patel, Anant B.

doi:10.1016/j.biopsych.2013.09.024

Cited by 118 publications

(88 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, in rats expressing a depressive-like behavior, cell activity measured by c-Fos immunoreactivity was decreased in the ventromedial PFC (Lim et al 2015). These data were supported by a study showing a decrease in both the excitatory and inhibitory neuronal functions in the PFC and a disturbed neurotransmitter homeostasis in the social defeat mouse model of depression (Veeraiah et al 2014). …”

Section: Brain Regions and Neurocircuits Involved In Depression: Neursupporting

confidence: 55%

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

et al. 2018

View full text Add to dashboard Cite

Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory.

show abstract

Section: Brain Regions and Neurocircuits Involved In Depression: Neursupporting

confidence: 55%

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A potentially alternative mechanism of action of clemastine, as a muscarinic receptor antagonist, was suggested by the activation of Akt/mammalian target of rapamycin (mTOR) pathways induced in synaptoneurosomes by scopolamine, a nonselective muscarinic antagonist (Voleti et al, 2013;Navarria et al, 2015). The Akt/mTOR pathway is a well characterized positive regulator of oligodendrocyte differentiation and myelination Wahl et al, 2014). Therefore, similar signaling pathways could be activated in oligodendrocytes following clemastine treatment, which directly results in OPC differentiation and myelination.…”

Section: Discussionmentioning

confidence: 99%

“…It is widely accepted that exposure to stress in rodents altered neuronal activity in the PFC and resulted in depressive-like behavior (Covington et al, 2005(Covington et al, , 2010Veeraiah et al, 2014). Selective activation of neurons in PFC through optogenetic stimulation provided an antidepressant effect in a mouse model of depression (Covington et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…However, one caution should be made when interpreting our results as we cannot exclude the possibility that clemastine-induced myelination and OPC differentiation could be a secondary effect of the drug on the neuronal circuitry. Systemic as well as local infusion of scopolamine had been previously shown to increase neuronal activity in the PFC by altering glutamate transmission and provided an antidepressant effect in the forced swim test of mice (Voleti et al, 2013;Navarria et al, 2015). Therefore, although specific PFC circuitry was not activated by "exogenous" social stimuli, neuronal activity could be altered through clemastine uptake, which in turn resulted in myelination enhancement.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

et al. 2016

View full text Add to dashboard Cite

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.

show abstract

“…Studies in animal models have confirmed these glutamatergic impairments in the context of anxiety-depression. Glutamatergic as well as gabaergic reduced activity has been observed in social defeated-mice (Veeraiah et al, 2014). Chronic unpredictable stress has been shown to impair long term potentiation in the thalamus–prefrontal cortex pathway (Quan et al, 2011) and in the hippocampus–prefrontal cortex connection (Cerqueira et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

et al. 2017

View full text Add to dashboard Cite

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT) and in the Chronic Mild Stress (CMS) model in rats. Four doses of S 47445 (0.3 to 10 mg/kg, oral route, 4 and 5 weeks, respectively) were assessed in both models. In mouse, behavioral effects were tested in various anxiety-and depression-related behaviors : the elevated plus maze (EPM), open field (OF), splash test (ST), forced swim test (FST), tail suspension test (TST), fur coat state and novelty suppressed feeding (NSF) as well as on hippocampal neurogenesis and dendritic arborization in comparison to chronic fluoxetine treatment (18 mg/kg, p.o.). In rats, behavioral effects of S 47445 were monitored using sucrose consumption and compared to those of imipramine or venlafaxine (10 mg/kg, i.p.) during the whole treatment period and after withdrawal of treatments. In a mouse model of genetic ablation of hippocampal neurogenesis (GFAP-Tk model), neurogenesis dependent/independent effects of chronic S 47445 treatment were tested, as well as BDNF hippocampal expression. S 47445 reversed CORT-induced depressive-like state by increasing grooming duration and reversing coat state’s deterioration. S 47445 also decreased the immobility duration in TST and FST. The highest doses (3 and 10 mg/kg) seem the most effective for antidepressant-like activity in CORT mice. Furthermore, S 47445 significantly reversed the anxiety phenotype observed in OF (at 1 mg/kg) and EPM (from 1 mg/kg). In the CMS rat model, S 47445 (from 1 mg/kg) demonstrated a rapid onset of effect on anhedonia compared to venlafaxine and imipramine. In the CORT model, S 47445 demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons at doses inducing an antidepressant-like effect. It also corrected CORT-induced deficits of growth and arborization of dendrites. Finally, the antidepressant/anxiolytic-like activities of S 47445 required adult hippocampal neurogenesis in the novelty suppressed feeding test contrary to OF, EPM and ST. The observed increase in hippocampal BDNF levels could be one of the mechanisms of S 47445 responsible for the adult hippocampal neurogenesis increase. Altogether, S 47445 displays robust antidepressant-anxiolytic-like properties after chronic administration through neurogenesis dependent/independent mechanisms and neuroplastic activities. The AMPA-PAM S 47445 could have promising therapeutic potential for the treatment of major depressive disorders or generalized anxiety disorders.

show abstract

Dysfunctional Glutamatergic and γ-Aminobutyric Acidergic Activities in Prefrontal Cortex of Mice in Social Defeat Model of Depression

Cited by 118 publications

References 51 publications

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

Contact Info

Product

Resources

About