Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents

Abstract

Basic and clinical studies demonstrate that stress and depression are associated with atrophy and loss of neurons and glia, which contribute to the decreased size and function of limbic brain regions that control mood and depression, including the prefrontal cortex and hippocampus. Here, we review findings that suggest that opposing effects of stress and/or depression and antidepressants on neurotrophic factor expression and signaling partly explain these effects. We also discuss recent reports that suggest a possible role for glycogen synthase kinase 3 and upstream wingless (Wnt)-frizzled (Fz) signaling pathways in mood disorders. New studies also demonstrate that the rapid antidepressant actions of NMDA receptor antagonists are associated with activation of glutamate transmission and induction of synaptogenesis, providing novel targets for a new generation of fast-acting, more efficacious therapeutic agents.

Figure 1. Signaling pathways regulated by chronic antidepressant treatments

Typical antidepressants, such as SSRIs, block monoamine reuptake by the 5-HT transporter (SERT). This leads to regulation of postsynaptic G protein coupled receptors, which couple to a variety of second messenger systems, including the cAMP-PKA-CREB pathway [4, 6] These effects require chronic SSRI treatment, due to the requirement for desensitization of 5-HT autoreceptors, and because 5-HT is a neuromodulator that produces slow neuronal responses. In contrast, glutamate produces fast excitation of neurons via stimulation of ionotropic receptors, including AMPA and NMDA receptors, resulting in depolarization and rapid intracellular signaling, such as induction of Ca^2+-calmodulin dependent protein kinase (CAMK). Glutamate and 5-HT signaling lead to regulation of multiple physiological responses including regulation of synaptic plasticity, as well as gene expression. One target of antidepressant treatment and CREB signaling is BDNF [16]. BDNF transcripts may remain in the soma or are targeted for transport to dendrites where they are subject to activity-dependent translation and release. A common BDNF polymorphism, Val66Met, which is encoded by G196A, blocks the trafficking of BDNF to dendrites [44, 45]. The induction of BDNF and other neurotrophic factors contributes to the actions of antidepressant treatments, including neuroprotection, neuroplasticity, and neurogenesis.

Figure 2. BDNF-TrKB signaling pathways

BDNF binding to the extracellular domain of TrkB induces dimerization and activation of the intracellular tyrosine kinase domain [30]. This results in autophosphorylation of tyrosine residues that then serve as sites for interaction with adaptor proteins and activation of intracellular signaling cascades, including the Ras- microtubule associated protein kinase (MAPK), phosphatidyl inositol-3 kinase (PI3K)/ serine threonine kinase (Akt), and phospholipase C (PLC)-γ pathways. Phosphorylation of tyrosine 515 of TrkB leads to recruitment of the Src homology 2 domain containing (Shc) adaptor protein, followed by recruitment of Growth factor receptor-bound protein 2 (Grb2) and son of sevenless (SOS) and activation of the Ras-MAPK pathway (right). Shc-Grb2 can also lead to recruitment of Grb2-associated binder-1 (GAB1) and activation of the PI3K-Akt pathway (left). Phosphorylation of the TrkB tyrosine residue 816 results in recruitment of PLCg, which leads to the formation of inositol triphosphate (IP3) and regulation of intracellular Ca²⁺ and diacylglycerol (DAG), which activates CAMK and protein kinase C (PKC). These pathways control many different aspects of cellular function, including synaptic plasticity, survival, and growth/differentiation. Basic and clinical studies demonstrate that BDNF and components of the Ras-MAPK and PI3K-Akt pathways are decreased by stress and depression, and increased by antidepressant treatments [16, 66, 67]. Abbreviations: ERK, extracellular signal regulated kinase; MEK, MAP/ERK kinase; MKP1, MAP kinase phosphatase 1; PDK1, 3-phosphoinositide-dependent protein kinase 1.

Figure 3. Signaling pathways involving Wnt-Fz and GSK3

Wnt is a secreted protein that binds to Fz, a seven transmembrane spanning domain receptor and a co-receptor for low-density lipoprotein receptor-related protein 5 (LRP5). Activation of Wnt leads to activation of Dvl and inhibition of GSK3. The activity of GSK3 is decreased by phosphorylation, which can occur via a number of different kinases, most notably Akt. One of the key targets of GSK3 is b-catenin (β-Ctnn), which is targeted for proteosomal degradation [97]. b-catenin can be translocated to the nucleus, where it enhances gene transcription via interactions with TCF/LEF, or it can have structural actions at the cell membrane. The activity of GSK3 is inhibited by the mood stabilizing agent lithium and by a number of other signaling pathways, most notably Akt [76]. Lithium also blocks GSK3 via disruption of an Akt/b-arrestin2/PP2A complex that keeps Akt in a dephosphorylated and inactive form [86]. G protein coupled receptors, including 5-HT1A can also influence GSK3 via this mechanism. GSK3 is also blocked by a number of other signaling pathways that produce antidepressant responses.

Figure 4. Signaling pathways underlying the rapid antidepressant actions of ketamine

Ketamine rapidly increases extracellular glutamate, resulting in fast excitation/depolarization [112]. Studies in cultured neurons demonstrate that this leads to activation of voltage-dependent Ca²⁺ channels (VDCC) and activity-dependent release of BDNF, which subsequently stimulates TrkB and downstream signaling pathways (PI3K-Akt and Ras-MAPK) [90]. These pathways stimulate mTOR signaling and the mTOR complex 1 (mTORC1), which increases S6 kinase (S6K, a member of the ribosomal S6 kinase family) and local translation of transcripts, including expression of synaptic proteins, postsynaptic density-95 (PSD95) and the AMPA receptor GluA1 subunit. GluA1-containing AMPA receptors are subsequentially inserted into the membrane, contributing to synaptogenesis. Ketamine-induction of mTOR signaling and behavioral responses are blocked by inhibition of AMPA receptors, PI3K-Akt, or MEK-ERK [9, 114]. In addition, the synaptogenic and behavioral actions of ketamine are blocked by rapamycin, a selective inhibitor of mTOR, and in BDNF Val66Met knock-in or BDNF conditional deletion mice [9, 56, 115]. Ketamine also increases the phosphorylation of GSK3 via an unknown mechanism [89], possibly by stimulation of Akt and/or S6K.