Modeling treatment-resistant depression in the preclinical setting

Synaptic dysfunction in depression

Preclinical models have demonstrated that AD mechanisms work on a backdrop of synaptic dysfunction induced through various exposures, including chronic stress and/or inflammation, and accelerated by underlying genetic vulnerabilities ( ). Neurons and glia make up the majority of cells in the brain and form complex neural circuits. Effective communication within these circuits requires highly integrated electrochemical signaling, which depends on efficient and effective synaptic communication. At the synapse, stored neurotransmitters are released and bind to receptors on pre- and postsynaptic membranes to trigger intracellular changes and ongoing propagation of the electrochemical signal throughout the circuit. The brain’s highly adaptive nature enables active synapses to become strengthened, thereby increasing the efficiency of signal transduction along this same pathway in the future, while inactive synapses are pruned, effectively whittling away unused connections. In depression, this process is maladaptive, with excessive synaptic pruning occurring in specific brain regions such as the prefrontal cortex (PFC) and hippocampus ( ; ). This disrupts activity within the mesocorticolimbic mood regulatory circuit to impact a range of essential functions, including motivation, perception, cognition, and emotion regulation ( ; ). Recent work suggests that both long-term activity-dependent changes in synaptic strength (synaptic plasticity) and shifting set points for these that result in relatively “hard-wired” changes that persist over the longer term (metaplasticity) and are essential for establishing or reversing neurobiological adaptations contributing to depression ( Fig. 5.1 ).

Synapses are situated on dendritic spines, which are dynamic structures that functionally serve as the locus of long-term synaptic plasticity ( ). At the tip of most dendritic spines, there is a dense region that harbors glutamate receptors and other protein complexes, namely a postsynaptic density (PSD), or postsynaptic synapse ( ). The size of a dendritic spine is proportional to the size of its PSD, the number of glutamate receptors, and, in turn, the synaptic strength or capacity for synaptic communication. For example, the volume of the spine-head is directly proportional to the number of postsynaptic receptors ( ), and the presynaptic number of docked vesicles ( ). Synaptic plasticity modifies information flow throughout the circuit and the consequent cognitive and behavioral outputs. Prolonged exposure to stress and inflammation dynamically regulate dendritic complexity, particularly within the PFC and hippocampus, regions that play an important role in the depression circuit ( ; ; ). The loss of synaptic connectivity in these critical nodes of the mood circuit profoundly impacts mood and cognitive function. This inability to maintain synaptic integrity and plasticity in depression represents a failure of one of the most fundamental and critical functions of the brain, namely the ability to communicate and store information and make appropriate, adaptive, and efficient responses to subsequent inputs ( ). While this critical brain function has been best studied for its role in learning and memory, it is now clear that it also plays a crucial role in the pathophysiology of depression and serves as the underlying mechanism of AD action ( ; ; ; ). Failure to effectively engage this mechanism is now thought to underlie the poor clinical response profiles observed in TRD ( ). The reasons for this target engagement failure are likely many and varied. Preclinical models will be critical for both the discovery of these rate-limiting mechanisms and their translation into innovative biomarker and treatment strategies for the clinic.

Antidepressant regulation of synaptic plasticity

Antidepressant treatments elicit region-specific structural changes via the induction of dendritic arborization, spinogenesis, improved cell survival, enhanced hippocampal neurogenesis, angiogenesis, and gliogenesis, a dynamic process known as synaptic plasticity ( ; ). Synaptic plasticity is an essential neurobiological mechanism that plays a vital role in brain development, maturation, and ongoing life-long learning processes and is implicated in several major neuropsychiatric and neurodegenerative disorders ( ; ; ). Synaptic plasticity occurs in part through activity-dependent, long-lasting modifications of synaptic strength, more commonly referred to as long-term potentiation (LTP) and long-term depression (LTD). The strengthening of synapses through LTP is triggered by N -methyl- d -aspartate (NMDA) receptors (NMDARs). A large NMDAR-dependent increase in dendritic spine calcium concentrations leads to activation of intracellular signaling cascades involving several protein kinases, most importantly Ca ^{2 +} /calmodulin-dependent protein kinase (CaMK). This leads to increased single-channel conductance of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPARs) and synaptic proteins such as PSD-95. In parallel, structural changes within the synapse occur, such that the size of the PSD and dendritic spine are increased, leading to an increase in synaptic strength, maintenance and ultimately impacting synaptic plasticity ( Fig. 5.2 ).

Classical ADs elicit plasticity via three main routes: receptor blockade, reuptake inhibition, and inhibition of enzymes that degrade monoamines, particularly monoamine oxidase. The resulting excess of monoamine neurotransmitter availability at the synapse results in the regulation of postsynaptic G protein-coupled receptors (metabotropic receptors), which couple to a variety of second messenger systems, including the cAMP-protein kinase A (PKA)-cAMP response element-binding (CREB) pathway ( ). These actions result in slow adaptive processes that impact gene transcription and brain-derived neurotrophic growth factor (BDNF) signaling to ultimately alter synaptic regulatory elements that work to restore monoamine balance at the synapse ( ; ; ; ; ).

In contrast, rapid-acting ADs such as ketamine, which functions as an NMDAR antagonist, enable synaptic plasticity via more direct activation of neurotrophic mechanisms ( ). A distinct difference between ketamine and slower-acting classical ADs is that ketamine triggers a rapid (within hours) upregulation of growth factor signaling and dendritic spine development in the PFC ( ; ). Studies have provided evidence of ketamine activation of AMPAR, an ionotropic transmembrane glutamate receptor that mediates fast synaptic transmission and is essential for the generation of LTP. The activation of AMPAR leads to the release of BDNF and downstream activation of growth and metabolic signaling cascades, such as the phosphoinositide 3-kinase (PI3K/Akt/mTOR) signaling pathway and the MAPK/ERK signaling pathway in the limbic system to mediate AD effects ( ). The downstream actions of AMPA receptor activation lead to an increase in neurotrophins such as brain-derived neurotrophic factor (BDNF) levels and activation of its receptor tropomyosin receptor kinase B (TrkB) ( Fig. 5.2 ).

Neurogenesis

Antidepressants stimulate the generation of newborn neurons from neural stem cells in the adult hippocampus, a process known as neurogenesis ( ; ), which takes about 4 weeks to form synaptic connections ( ) and contributes to antidepressant-like effects in rodents ( ; ; ). In mammals, this process is limited to select regions, the best-studied of which is the subgranular layer of the dentate gyrus of the hippocampus. Herein, adult newborn neurons are formed from quiescent neural progenitor stem cells, which differentiate into mature granule cells, which become integrated into the existing hippocampal circuitry. It is becoming increasingly clear that neurogenesis in the hippocampus and other regions plays a key role in both the pathophysiology and treatment of mood disorders ( ; ). There is a significant reduction in hippocampal volume in depressed relative to healthy subjects ( ; ), with contrasting increases in volume in other regions, including the amygdala ( ). Such structural differences are confirmed in postmortem studies, demonstrating, for example, more significant reductions in hippocampal histological sections from depressed patients relative to control subjects ( ).

Hippocampal overexpression of neurotrophic signaling factors BDNF or CREB mimics both the structural and behavioral effects of sustained antidepressant treatment ( ). In line with this, studies have shown that antidepressant drugs, including tricyclic antidepressants and selective serotonin reuptake inhibitors, increase neuronal proliferation in the dentate gyrus when administered chronically ( ). However, the rate of cell proliferation and programmed cell death in the dentate gyrus of mice chronically treated with antidepressants does not appear to be dependent on BDNF. However, activation of the BDNF receptor TrkB is essential for the long-term survival of newborn neurons ( ). These effects are dependent on chronic administration of antidepressant therapy, consistent with the time course of antidepressant treatments ( ). This suggests that the regulations of BDNF and TrkB are involved in antidepressant treatment response and that this is directly reversing a critical pathophysiological feature of the illness. Whether this is a common mechanism of AD response remains to be determined.