Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Abstract

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but there are high rates of partial- or non-response and the delayed onset of the effects of antidepressant leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry essential for mood regulation and cognitive function. Although current antidepressants such as serotonin reuptake inhibitors produce subtle changes that take effect in weeks or months, new agents have recently shown improvement in mood ratings within hours of dosing in patients resistant to typical antidepressants. These new agents have also been shown to reverse the synaptic deficits caused by stress within a similar time scale.

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

“…2). However, Zanos et al found that both ketamine and (2R,6R)-HNK have no significant effect on mTOR phosphorylation and BDNF levels at 1 h after treatment, which is not consistent with previous studies regarding the involvement of AMPAR-mediated BDNF/TrkB/mTORC1 (mammalian target of rapamycin complex 1) signaling in the rapid antidepressant effects of ketamine [20,21,26] (Fig. 1).…”

“…Ketamine is widely accepted to act mainly by inhibiting NMDARs in GABAergic interneurons, thus disinhibiting glutamatergic neurons, leading to the activation of downstream signaling and synaptic protein synthesis [20][21][22] (Fig. 1).…”

“…The antidepressant effects of ketamine require the activation of several intracellular signaling pathways [15,23,24] and the enhancement of AMPAR-mediated synaptic plasticity [20,25]. The authors examined the biochemical profiles of ketamine and (2R,6R)-HNK in the hippocampus and medial prefrontal cortex, two moodrelated brain regions.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Increased extrasynaptic glutamate can also bind to presynaptic neuronal metabotropic mGluR2/3 autoreceptors inhibiting glutamate release leading to chronic reductions in intrasynaptic glutamate, loss of excitatory synaptic activity, and ultimately result in synaptic loss (Duman, 2014;Duman et al, 2016;McEwen et al, 2016). Of note, mGluR2/3 antagonists have demonstrated ketamine-like antidepressant effects (Duman, 2014;McEwen et al, 2016).…”

Involvement of Brain 5-HT7 Receptors in the Formation of Stress Adaptation in Mice

“…46 Importantly, these 5-HT 7 receptor-mediated molecular and cellular mechanisms that have been shown to be involved in neuronal plasticity and morphology are consistent with the new insights into neurobiology of stress and mood disorders. 47 Taken together, these findings suggest that further detailed studies focused on neuronal plasticity and morphology, which may be modulated by the 5-HT 7 receptor, may be useful for understanding the mechanisms of stress adaptation.…”