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Written by: Wang Shu
whose molecular etiology is unknown.
Studies at different molecular levels have shown that the pathogenesis of depression involves a variety of highly complex and interrelated metabolic pathways, including monoamines, HPA axes, neurotrophic factors and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, epigenetics, inflammation, opioid system, myelination, and gut-brain axis
.
An article published in the journal Mol Psychiatry on October 6, 2022 by Theo Rein of the Max Planck Institute of Psychiatry in Germany comprehensively summarizes the six major pathogenesis hypotheses of depression, elucidating how signaling pathways and molecular systems interact in depression, and how each pathway or system relates
to synaptic transmission.
Figure 1: Molecular mechanisms of depression
1
The monoamine hypothesis
The initial evidence supporting the "monoamine hypothesis for depression" was that monoamine oxidase inhibitors and tricyclic antidepressants could improve depressive symptomsby enhancing the activity of serotonin and norepinephrine.
Although there have been many studies to support this hypothesis, the downside is that antidepressants usually take weeks to clinically act, while drugs can raise monoamine levels
almost instantaneously.
In addition, approximately one-third of patients with depression do not respond to antidepressants that act only by inhibiting monoamine reabsorption, and limiting the availability of tryptophan, a serotonin precursor, does not induce a depressive episode
in all patients.
Therefore, the monoamine deficiency hypothesis may not be widespread in depressed patients, suggesting that other pathways and neurotransmitters are associated with
depression.
Depression is associated with other neurotransmitter disorders in the brain, cerebrospinal fluid, and peripheral tissues, including GABA and glutamatergic systems
.
Depressed patients have reduced
glutamate levels in specific brain regions.
Therefore, newly developed antidepressant treatments focus on reversing glutamate and GABA deficiencies
by targeting AMPA receptors or type 2 metabolic glutamate receptors.
This has also led to the discovery
of rapid antidepressants such as ketamine.
In basic and clinical studies, ketamine rapidly increases glutamate signaling, producing rapid, sustained antidepressant effects
.
Ketamine increases the overall activity
of the prefrontal cortex by blocking NMDA receptors and thus excitatory glutamate signaling in GABAergic neurons.
Monoamines not only directly affect synaptic nerve transmission, but also indirectly affect intracellular pathways
through their G protein-coupled receptors.
Among them, opioid receptors interact functionally with
5-HT and dopamine receptors through heterodimeration.
A large body of clinical and preclinical evidence suggests the involvement of opioid receptors in MDD pathology
.
Opioid receptors negatively regulate neurotransmitter release and excitability of neurons by activating G protein-mediated mechanisms, resulting in enhanced potassium channel function, cellular depolarization, inhibition of voltage-gated calcium channel function, and negative regulation of neurotransmitter release, further affecting neuronal activity and plasticity
.
Figure 2: Receptor-related signaling pathways of serotonin, opioids, and BDNF regulate neuronal activity and synaptic function
2
The neurotrophic factor hypothesis
The "neurotrophic hypothesis for depression" suggests that disruption of neurotrophic support is a key mechanismof MDD-related synaptic and brain-related functional changes.
Neurotrophic factors are responsible for neuronal network formation, support, and plasticity
.
Among them, BDNF is an important member of the neurotrophic factor family, which can activate tropomyosin-associated kinase (Trk) and p75 receptors
.
Numerous studies have shown a decrease
in blood levels of neurotrophic factors in patients with persistent depression and relapse, in animal models of depression.
Notably, antidepressant therapy and electroconvulsive therapy increased BDNF levels
.
Traditional and rapid antidepressants not only require BDNF expression and its downstream signaling to take effect, but also antidepressants can directly bind to the transmembrane domain of TrkB dimer to form stable conformations of multi-protein complexes and promote the binding
of TrkB and BDNF.
Through the Trk receptor, neurotrophic factors can activate cell signaling pathways that regulate cell fate, axon growth, dendritic growth and pruning, and overall normal neuronal function
.
One of the most significant roles of BDNF is to promote hippocampal adult neurogenesis, which may play a role
through most of the signaling described above.
Hippocampal neurogenesis defects in MDD are associated
with a decrease in hippocampal size and volume, a decrease in the number of neurons and glial cells, and a decrease in cell size found at autopsy.
Significant correlations have been found between neurogenesis and synaptic activity, including long-term enhancement (LTP).
Adult neonatal neurons can regulate dendritic spike density and excitatory synaptic transmission
by reassigning existing synapses.
Importantly, antidepressants induce neurogenesis, increase plasticity, and reverse hippocampal atrophy
.
3
HPA axis hypothesis
for depression.
The HPA axis is key
to coordinating the body's stress response.
The body terminates the stress response
by activating the negative feedback mechanism of glucocorticoid receptors (GRs) by stress-secreted glucocorticoids.
Elevated cortisol levels, HPA hyperactivity, and dysfunction
of negative HPA axis feedback have been found in some patients with depression.
Therefore, multiple drugs targeting the HPA axis have been developed to treat depression, including corticosteroid synthesis inhibitors, GR antagonists, adrenocorticotropin-releasing hormone receptor antagonists
.
Stress induces atrophy of the cerebral dendritic apex and postsynaptic dendritic spines, resulting in significant synaptic remodeling
.
Mechanically, glucocorticoids increase the pool
of easily released glutamate vesicles in the prefrontal cortex by activating membrane receptors.
The synaptic and behavioral effects of stress are also mediated
through the opioid system.
Signal transduction of glucocorticoids interacts with most depression-related pathways such as BDNF, FKBP51, and autophagy pathways
.
Figure 3: Stress signals are intertwined with multiple depression-related pathways
4
The cytokine hypothesis
.
Persistent immune responses, such as infections, malignancies, or autoimmune diseases, can lead to depression
.
In fact, an enhanced inflammatory response is associated with
MDD.
Specific pro-inflammatory cytokines and their receptors associated with MDD include IL-6, TNF-α, IL-1β, IL-2, IL-2, IL-2 receptors, IL-4, IL-10, IL-1 receptor antagonists, transforming growth factor-β, and c-reactive protein (CRP).
Pro-inflammatory cytokines are also associated
with MDD severity.
Many mechanisms have been proposed to explain the occurrence of inflammation in MDD, including inflammasome signaling pathways, oxidative stress, changes in BBB permeability, and the entry of peripheral immune cells into the brain
.
Mechanisms by which inflammatory pathways affect synaptic activity include pro-inflammatory cytokines regulating the expression of NMDA and AMPA receptor subunits, reducing AMPA receptor phosphorylation, and ultimately affecting glutamate synapses and LTP-related processes
.
The immune system is closely related to the neuroendocrine system, and glucocorticoids exert pro- or anti-inflammatory effects in
different situations.
In addition, increased inflammatory mediators in MDD can significantly interfere with mitochondrial oxidative phosphorylation and ATP production, ultimately leading to increased
oxidative stress.
5
The mitochondrial hypothesis and oxidative stress hypothesis
in mitochondrial dynamics (fusion, division, mitophagy).
Mitochondrial dysfunction also produces free radicals and oxidative stress
.
Markers of oxidative stress are elevated in depression, while antioxidant capacity is reduced
.
In addition, as the disease progresses, mitochondrial dysfunction and oxidative damage develop
progressively.
Therefore, the "oxidative stress hypothesis of depression" proposes that oxidative stress is the cause of
brain structural changes in patients with depression.
Normal levels of reactive oxygen species (ROS) are important signaling molecules that play a key role
in neuronal cell function.
However, when at high levels and low in the presence of antioxidants, ROS can be harmful
to neurons and LTP.
Increased oxidative stress may lead to further mitochondrial damage, increased apoptosis, and ultimately inflammatory signaling
.
Mitochondria regulate synaptic function and plasticity in a variety of ways, including ATP production, Ca2+ buffering and signaling, neurotransmitter synthesis, establishment and maintenance of membrane excitability, and regulation of synaptic vesicle pools and neurotransmitter release
.
Mitochondria can produce oxygen and nitrogen needed for synaptic plasticity and activate caspase in dendrites, inducing the clearance
of postsynaptic dendritic spines.
Figure 4: The role of mitochondrial dysfunction in depression and its impact on synaptic function
6
The "microbial-gut-brain axis" hypothesis
in the gut microbiome in MDD.
Conversely, supplementation with probiotics or the Mediterranean diet has an antidepressant effect
on patients.
A causal relationship between microbiome alterations and depression-like behavior can also be confirmed
from fecal bacteria transplantation microbiota or specific bacterial experiments.
Microorganisms affect brain activity
by regulating synaptic function through specific molecules.
A typical example is the kynurenine pathway, which is a metabolite
of the essential amino acid tryptophan.
Tryptophan is one of
the first nutrients reported (more than 60-80 years ago) associated with depression.
The conversion of tryptophan to the neurotransmitter serotonin is clearly associated
with synaptic function and depression.
However, tryptophan mainly produces neurotoxic (e.
g.
, quinolinic acid) and neuroprotective (e.
g.
, kynurinic acid) metabolites
primarily through kynurenine metabolic pathways.
By binding to glycine binding sites, kynuuric acid acts directly on synapses
as a glutamate receptor antagonist.
Quinolinic acid, on the other hand, is a glutamate receptor agonist, which enhances the release of glutamate and inhibits the reuptake
of glutamate by astrocytes.
Figure 5: Illustration of the role of gut microbes and their metabolites in depression - kynurenine pathway
summary
This review summarizes the molecular connections
between the main pathways and systems that contribute to the development and progression of depression.
The relative contribution of each pathway varies between individual patients, reflecting the high complexity
of the disease.
It is
unrealistic to fully understand the association of multiple molecular pathways with MDD.
【References】
1.
Fries, G.
R.
, Saldana, V.
A.
, Finnstein, J.
et al.
Molecular pathways of major depressive disorder converge on the synapse.
Mol Psychiatry (2022).
https://doi.
org/10.
1038/s41380-022-01806-1
The images in the article are from references
