Molecular pathways of major depressive disorder converge on the synapse

Abstract

Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD's neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, emotion, and conscience we can conceptualize, each pathway or molecular system will be scrutinized for links to synaptic neurotransmission. Models of the neurobiology of MDD will be discussed as well as future actions to improve the understanding of the disease and treatment options.

Fig. 1. Simplified scheme of the molecular basis of consciousness/depression.

The pattern of synaptic activity is regarded as the closest correlate or representation of consciousness and mood, and thus also depression. This review describes selected pathways with established links to depression with a focus on their links to synaptic activity as well as their interrelatedness.

Fig. 2. Signaling pathways through the receptors of serotonin, opioids, and BDNF alter neuronal and synaptic functions.

Signaling through a variety of receptors is highly intertwined and may produce significantly overlapping effects on neurogenesis, neuronal structure, and synaptic activity. Activation of these pathways may be imbalanced in major depressive disorder (MDD), and at least partly restored by pharmacological treatments targeting various facets of these pathways. AC adenyl cyclase, Akt protein kinase B, BDNF brain-derived neurotrophic factor, CamKII Ca²⁺/Calmodulin-dependent protein kinase II, CREB cAMP responsive element binding protein, DAG diacylglycerol, ERK extracellular signal-regulated kinase, Gα/βγ G-protein subunits α/βγ, GSK3β glycogen synthase kinase 3β, 5-HTR serotonin receptor, IP3 inositol 1,4,5-trisphosphate, MAPK mitogen-activated protein kinase, µOR µ-opiod receptor, mTOR mammalian target of rapamycin, NT neurotransmitters, PI3K phosphoinositide-3-kinase, PKA protein kinase A, PLCγ phospholipase C γ, TrkB tyrosine receptor kinase B, TRPC3 transient receptor potential canonical subfamily 3.

Fig. 3. Stress signaling is interwoven with numerous depression-relevant pathways.

The levels of the stress hormone cortisol are set by the hypothalamus-pituitary-adrenal (HPA) axis. They activate GR, which exerts both genomic and non-genomic actions. Of the GR-regulated genes, BDNF, FKBP51 and SGK are displayed, including examples of their links to various pathways, physiological systems (metabolism, inflammation, neuronal and secretory autophagy and HPA axis) and activity of synaptic proteins (receptor recycling, vesicle docking and recycling, ion channels). ACTH adrenocorticotropic hormone, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, CRH corticotropin-releasing hormone, Dnmt1 DNA methyltransferase 1, ERK extracellular regulated kinase, FKBP FK506-binding protein, GR glucocorticoid receptor, MM9 matrix metalloproteinase 9, mTOR mammalian target of rapamycin, NFκB nuclear factor kappa B, NMDAR N-methyl-D-aspartate receptor, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, Rab ras related protein, RRP readily releasable pool, SGK serum/glucocorticoid regulated kinase, TrkB tropomyosin-related kinase B, TRPC3 transient receptor potential channel 3.

Fig. 4. Theoretical model explaining the role of mitochondrial dysfunction and its effects on synaptic function in major depressive disorder (MDD).

Disrupted mitochondria can lead to the activation of apoptosis and subsequent release of damage-associated molecular patterns (DAMPs), ultimately reinforcing inflammatory mechanisms. The resulting oxidative stress can also be associated with the accelerated aging phenotype consistently reported in MDD patients.

Fig. 5. Kynurenine pathway exemplifying the role of metabolism and gut microbes in MDD.

The conversion to serotonin takes place on the enterochromaffin cells of the intestinal mucosa, but also in the CNS. The kynurenine pathway produces numerous compounds that impact synaptic function either directly or indirectly through their influence on multiple systems, including immune function and oxidative stress. Conversely, these systems also shape the activity of several enzymes involved in the kynurenine pathway, in combination with diet and gut microbiota composition. TRP tryptophan, KYN kynurenine, 3HK 3-hydroxykynurenine (neurotoxic), KYNA kynurenic acid (neuroprotective), 3HAA 3-hydroxyanthranilic acid (neurotoxic), AA anthranilic acid, QUIN quinolinic acid (neurotoxic), PIC picolinic acid (neuroprotective), 5-HT serotonin, 5-HTR serotonin receptor, 5-HTT serotonin transporter, ILA indole-3-lactic acid, IPA indole-3-propionic acid.

Fig. 6. Multitude of molecular pathways and physiological systems determining mental health.

The pattern of synaptic activity representing mood, behavior, consciousness, and thus also major depressive disorder (MDD), is governed by the concerted action of interrelated molecular pathways and physiological activities. This review exemplified molecular links between major systems contributing to the development of MDD. The relative contribution of each pathway varies between individual patients as a reflection of the high complexity of the disease.