Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants

Abstract

Antidepressants that produce rapid and robust effects, particularly for severely ill patients, represent one of the largest unmet medical needs for the treatment of depression. Currently available drugs that modulate monoamine neurotransmission provide relief for only a subset of patients, and this minimal efficacy requires several weeks of chronic treatment. The recent discovery that the glutamatergic agent ketamine produces rapid antidepressant responses within hours has opened a new area of research to explore the molecular mechanisms through which ketamine produces these surprising responses. Clinical and preclinical findings have exposed some of the unique actions of ketamine and identified a cell-signaling pathway known as the mammalian target of rapamycin. Activation of mammalian target of rapamycin and increased synaptogenesis in the prefrontal cortex are crucial in mediating the antidepressant effects of ketamine. Importantly, the synaptic actions of ketamine allow rapid recovery from the insults produced by exposure to repeated stress that cause neuronal atrophy and loss of synaptic connections. In the following review, we explore some of the clinical and preclinical findings that have thrust ketamine to the forefront of rapid antidepressant research and unveiled some of its unique molecular and cellular actions.

Figure 1. Pyramidal neurons in the PFC with spine synapses and influence of stress and ketamine treatments

Top panel: shown on the left is a schematic displaying the rat mPFC. In the middle is an image of a neurobiotin-labeled layer V pyramidal neuron from rat mPFC; on the right is a diagram of a spine, with pre- and postsynaptic elements. Bottom panel: the influence of chronic stress exposure (21 d) without or with ketamine administration, compared to non-stressed controls, on apical dendrite spines in layer V pyramidal neurons of rat mPFC. (Adapted from 23).

Figure 2. Increases in mTOR signaling and synapse formation in response to treatment with rapid-acting antidepressants

Excitatory synapse before (Left) and after (Right) treatment with rapid-acting antidepressants. Decreases in inhibitory GABAergic signaling from interneurons induced by (a) NMDA receptor blockade or (b) M3 muscarinic receptor blockade lead to increased glutamate release from pyramidal neurons. Blockade of pre-terminal mGluR2 receptors (c) also leads to increased glutamate release. Activation of postsynaptic AMPA receptors by increased glutamate transmission or (d) direct acting Ampakines leads to depolarization, activation of voltage-dependent calcium channels and release of BDNF. BDNF binds TrkB receptors, leading to transphosphorylation and downstream activation of the ERK and Akt pathways and suppression of GSK-3, which can be augmented by (e) Lithium. These signaling events activate mTOR, leading to downstream phosphorylation of mTOR substrates, S6K and 4E-BP1. mTOR signaling activation leads to increase protein translation and synaptogenesis, mediating rapid antidepressant effects. See text for additional details of pathways leading to regulation of mTOR signaling, including the TSC1/2 complex.

Figure 3. Signaling mechanisms for the regulation of LTD and LTP: potential site of action for ketamine

LTP and LTD are distinct and opposing processes. During some forms of LTD, low levels of NMDA receptor activation lead to calcium influx and binding to calmodulin. Calcium/Calmodulin activates calcineurin (PP2B), which dephosphorylates and inactivates Inhibitor-1 leading to loss of PP1 suppression. PP1 dephosphorylates AMPA receptor subunits and can lead to receptor internalization. PP1 also dephosphorylates GSK-3 leading to its activation and suppression of mTOR. Blockade of NMDA receptors by ketamine may prevent low-level NMDA receptor activity and subsequent inhibition of mTOR, ultimately leading to activation of mTOR signaling and a synaptic bias toward LTP.