Studies on antidepressant-mediated regulation of signal transduction

Depression affects around 16% of the population at some point in their lives and major depressive disorder is a leading cause of disability worldwide. Depression is caused by an interaction of genetic and environmental factors, but the molecular and cellular mechanisms underlying its pathogenesis are not entirely clear. The monoamine hypothesis of depression, which involves imbalances in serotonergic, noradrenergic and possibly dopaminergic functions, has dominated notions and explanations of the pathophysiology of depression. Most clinically used antidepressants act by increasing the synaptic levels of these monoamines. While these treatments are beneficial in many cases, a large population of depressed patients do not respond, or respond suboptimal, to these current antidepressant treatments.

There is accumulating evidence that depression is associated with impairments of synaptic plasticity, dendritic arborization and cell proliferation/survival in hippocampus and frontal cortex and normalization of these processes could lead to antidepressant responses. The neurochemical mechanisms underlying these functional and structural impairments are poorly understood, but appear to involve changes in glutamate neurotransmission, neuropeptides, neurotrophins and intracellular signaling cascades.

The present studies used biochemical and behavioural techniques and found that the atypical antidepressant, tianeptine, which is a serotonin reuptake enhancer, increased phosphorylation of the GluA1 subunits of AMPA glutamate receptors both in brain slices and in intact animals. Antidepressant and stimulatory behavioral responses to tianeptine were attenuated in mice bearing point mutations at Ser831-/Ser845-GluA1. Acute elevated platform stress, known to inhibit synaptic plasticity in hippocampal→frontal cortex neurotransmission, was found to downregulate a putative BDNF/MEK/MAPK signaling cascade in frontal cortex which could be counteracted by tianeptine, imipramine and the glucocorticoid receptor antagonist mifepristone.

The serotonin receptors mediating the antidepressant effects of serotonin reuptake inhibitors, the currently most prescribed class of antidepressants, are not fully understood. Here, it is reported blockade of 5-HT6 receptors with the antagonist SB271046 counteracts the potentiating actions of fluoxetine on cortical phospho-Ser845-GluA1 and reduces its antidepressant-like behavioral action. Moreover, the 5-HT6 receptor agonist EMDT mimics antidepressant-like biochemical and behavioral effects of fluoxetine.

In conclusion, these studies have shown that the atypical antidepressant tianeptine can potentiate signaling cascades associated with synaptic plasticity and add further evidence that tianeptine acts as an enhancer of AMPA glutamate transmission. These studies also suggest, for the first time, a role for 5-HT6 receptors in mediating antidepressant responses.

List of scientific papers

I. Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, Spedding M, Roth BL, McEwen BS, Greengard P (2007). Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Eur J Neurosci. 26(12): 3509-17.
https://pubmed.ncbi.nlm.nih.gov/18088278

II. Qi H, Zhang X, Delagrange P, Spedding M, Svenningsson P (2009). Tianeptine increases phosphorylation of AMPA receptors and potentiates MAPK signalling. [Manuscript]

III. Qi H, Mailliet F, Spedding M, Rocher C, Zhang X, Delagrange P, McEwen B, Jay TM, Svenningsson P (2009). Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation. Neuropharmacology. 56(1): 37-46.
https://pubmed.ncbi.nlm.nih.gov/18657555

IV. Mailliet F, Qi H, Rocher C, Spedding M, Svenningsson P, Jay TM (2008). Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling. Exp Neurol. 211(2): 593-6.
https://pubmed.ncbi.nlm.nih.gov/18436212

V. Svenningsson P, Tzavara ET, Qi H, Carruthers R, Witkin JM, Nomikos GG, Greengard P (2007). Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. J Neurosci. 27(15): 4201-9.
https://pubmed.ncbi.nlm.nih.gov/17428998