This pathway illustrates the synaptic and intracellular signaling molecules implicated in major depressive disorder, spanning monoaminergic, glutamatergic, GABAergic, and neurotrophic systems at a tripartite synapse.

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Clinical context

Major depressive disorder is a leading cause of disability worldwide, characterized by anhedonia, low mood, fatigue, sleep and appetite disturbance, cognitive impairment, and feelings of guilt. Molecularly, these symptoms reflect converging disturbances across neurotransmitter, neurotrophic, and stress-response pathways at the synapse¹.

Monoaminergic signaling: 5-HT and the 5-HT1A receptor

As shown on the poster, serotonin (5-HT) signals through the 5-HT1A receptor, a G-protein–coupled receptor that inhibits adenylate cyclase and modulates downstream kinases including GSK3β. The historical monoamine hypothesis proposed that deficient serotonergic, noradrenergic, and dopaminergic tone underlies depressive symptoms — a view supported by the efficacy of monoamine oxidase inhibitors and tricyclic antidepressants, though their delayed clinical onset indicates that adaptive downstream signaling, not acute neurotransmitter elevation, mediates the therapeutic effect¹.

Glutamatergic signaling and the glutamate–glutamine cycle

Excitatory transmission at the depicted synapse is organized around the glutamate–glutamine cycle. In the presynaptic mitochondrion, glutaminase converts glutamine to glutamate, which is loaded into synaptic vesicles by the vesicular glutamate transporter (vGlut) and released via SNARE-mediated exocytosis. Released glutamate is taken up by glial glutamate transporters, converted back to glutamine by glutamine synthetase, and returned to the presynaptic terminal via glutamine transporters; a shuttle that sustains excitatory neurotransmission and prevents excitotoxic accumulation².

On the postsynaptic neuron, glutamate acts at ionotropic AMPA, NMDA, and kainate receptors, and at metabotropic mGluR1/5 receptors. AMPA receptor activation depolarizes the membrane and relieves the magnesium block on NMDA receptors, permitting Ca²⁺ influx that drives plasticity-related signaling. Disturbances in this system contribute to reduced synaptic strength and impaired responsiveness to emotional stimuli in MDD².

GABAergic inhibition

A GABAergic interneuron provides inhibitory input to the postsynaptic neuron, with GABA synthesized from glutamate by glutamic acid decarboxylase (GAD). Balanced GABAergic inhibition constrains pyramidal cell firing and shapes network oscillations; loss of interneuron function disrupts excitation/inhibition balance and is a recognized contributor to MDD pathophysiology².

Neurotrophic signaling: BDNF–TrkB–mTORC1

Brain-derived neurotrophic factor (BDNF) binds the TrkB receptor and activates parallel signaling branches central to synaptic plasticity. TrkB activation drives ERK and Akt signaling, with Akt converging on mTOR to promote neuroplasticity and synaptogenesis³. Local translation of BDNF itself is regulated by eEF2 kinase (eEF2K), which phosphorylates eEF2 to suppress general translation; relief of this suppression permits local BDNF synthesis and secretion at the synapse³. Nitrergic Rheb provides an additional input to mTOR, integrating nitric oxide signaling with translational control³.

This neurotrophic branch is the principal effector arm through which multiple upstream signals, monoaminergic, glutamatergic, and pharmacological, remodel synaptic connectivity in MDD³.

Reelin–APOE signaling through VLDLR and APOER2

Reelin and APOE act at the VLDLR and APOER2 receptors on the postsynaptic membrane, recruiting the adaptor DAB1 and activating Src family kinases (SFKs). Downstream signaling proceeds through PKB and inhibits GSK3β; unrestrained GSK3β activity contributes to tau phosphorylation and neurofibrillary tangle (NFT) formation. This branch links extracellular matrix and lipoprotein signaling to cytoskeletal integrity and synaptic stability, providing a mechanistic bridge between synaptic dysfunction and structural pathology relevant to MDD¹.

Stress signaling: the glucocorticoid receptor

cortisol under chronic stress. Sustained glucocorticoid signaling suppresses BDNF expression and destabilizes dendritic architecture, linking HPA axis activation to the neurotrophic and glutamatergic deficits shown elsewhere on the pathway².

Rapid-acting antidepressants: ketamine at the NMDA receptor

Ketamine exerts its rapid antidepressant effect by transiently blocking NMDA-mediated currents. This blockade disinhibits glutamatergic pyramidal neurons, produces a burst of glutamate release that engages AMPA receptors, and drives BDNF release. The resulting activation of the TrkB–Akt–mTOR axis, together with relief of eEF2K-mediated translational suppression, triggers rapid synaptogenesis, which is the molecular basis for ketamine's fast-onset clinical effect in treatment-resistant depression³.

Integrating the pathway

The molecules shown on this pathway do not operate in isolation. Monoaminergic, glutamatergic, GABAergic, neurotrophic, Reelin, and glucocorticoid signaling converge on shared intracellular effectors — most notably GSK3β, Akt, mTOR, and the translational machinery controlling local BDNF synthesis — that together determine synaptic strength, spine density, and network stability. Pharmacological agents targeting different entry points to this network can restore balance and produce clinical benefit, an insight that underpins current antidepressant drug development¹.

References

1. Fries, G.R., Saldana, V.A., Finnstein, J. et al. Molecular pathways of major depressive disorder converge on the synapse. Mol Psychiatry 28, 284–297 (2023).

1. Cui, L., Li, S., Wang, S. et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Sig Transduct Target Ther 9, 30 (2024).

1. Duman, R.S. & Li, N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Phil Trans R Soc B 367, 2475–2484 (2012).