Targeting metaplasticity mechanisms to promote sustained antidepressant actions

Abstract

The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.

Keywords: Event driven pharmacology; Metaplastogen; Neuroplastogen; Pivotal mind state; Psychoplastogen.

Figure 1.. Translatable metaplasticity concepts.

(A) Distinctions between plasticity and metaplasticity. (Top) Standard synaptic plasticity induction results in a quantitatively greater excitatory postsynaptic potential (EPSP) in response to the same stimulus (small arrow) after plasticity induction. This alteration in synaptic efficacy results in enhanced excitatory synaptic transmission and structural plasticity as illustrated in the pyramidal cell. (Bottom) In contrast, metaplasticity involves a priming stimulus persistently altering the threshold for a change in synaptic efficacy without changing basal synaptic transmission or neuronal morphology. An example is shown where the priming stimulus lowers the threshold for synaptic potentiation, leading to the same plasticity induction event eliciting a quantitatively greater evoked EPSP response and augmented structural plasticity compared to the response elicited without the priming stimulus. (B) Clinical relevance and advantages of targeting metaplastic mechanisms to promote sustained antidepressant effects. Following intravenous administration, ketamine is rapidly eliminated and side effects generally follow these pharmacokinetics. Acute antidepressant effects are typically observed after exposure and can extend for hours or days. Repeated ketamine administration elicits significantly greater antidepressant effects, and these effects typically persist longer than after a single administration [16, 20-22]. A single administration of ketamine leading to an enhanced antidepressant effect in response to the same treatment days later is consistent with the concept of metaplasticity where the first treatment lowers the threshold for persistent alterations in synaptic efficacy and neural morphology. Targeting metaplastic mechanism(s) to yield persistent antidepressant effects presents therapeutic benefits that may enhance patient compliance such as reduced dosing frequency and, thus, adverse responses because the necessity for the drug to be continuously present is eliminated. Created with Biorender.com

Figure 2.. Molecular mechanisms of NMDAR activation-dependent LTP.

Canonical NMDAR activation-dependent LTP induction is initiated by simultaneous AMPAR-mediated postsynaptic depolarization and glutamate binding to the NMDAR, facilitating NMDAR activation and Ca²⁺ influx after the release of an NMDAR Mg²⁺ block. LTP expression is instigated by Ca²⁺/calmodulin-dependent signaling that enables postsynaptic kinase activity (e.g., CaMKII, PKC) to promote enhanced synaptic transmission via numerous alterations including phosphorylation of glutamatergic receptors, trafficking of AMPARs to the postsynaptic membrane, and lateral diffusion of extrasynaptic AMPARs. Initiation of gene transcription is mediated by numerous signaling cascades (e.g., adenylyl cyclase-cAMP-PKA) and protein kinases (e.g., CaMKIV). LTP maintenance requires de novo protein synthesis either in the soma (e.g., CREB-dependent gene transcription and subsequent translation of proteins such as c-fos, Arc, AMPAR, NMDAR; BDNF-TrkB-mTORC1 also contribute) or translation of transcripts localized to dendrites, yielding long-lasting alterations in synaptic efficacy. Abbreviations: AC, adenylyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CaMKII, Ca²⁺-calmodulin-dependent protein kinase II; CaMKII, Ca²⁺-calmodulin-dependent protein kinase IV; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; LTP, long-term potentiation; mTORC1, mechanistic target of rapamycin complex 1; NMDAR, N-methyl-D-aspartate receptor; PKA, protein kinase A; PKC, protein kinase C; TrkB, tropomyosin receptor kinase B. Created with Biorender.com

Figure 3.. Strategies for targeting metaplastic mechanisms.

Results from preclinical studies suggest that the antidepressant-like effects of ketamine coincide with sustained, beneficial metaplasticity in brain regions implicated in the pathophysiology of depression. Numerous strategies can be used in envisioning ketamine mimetics that may leverage metaplastic mechanisms (metaplastogens) in a manner that coincides with rapid and prolonged antidepressant effects. 1. Disinhibition of glutamatergic neuron activity: Ketamine may work as an antidepressant by disinhibiting glutamatergic neurons via preferential inhibition of NMDARs localized to interneurons [17, 121]. Sustained metaplasticity and long-lasting antidepressant effects are observed after ketamine treatment. Administration of a subanesthetic dose of ketamine is proposed to preferentially block NMDARs localized to interneurons to disinhibit principal cell activity. Reducing the tone of GABAergic activity via negative allosteric modulation (NAM) may also yield similar results (e.g., α5 GABA NAM MRK-016 [11, 211]). 2. Increase probability of glutamate release: Hepatic metabolism of ketamine produces norketamine and, subsequently, hydroxynorketamines. (2R,6R)-HNK has been shown to rapidly enhance glutamatergic transmission via increased probability of glutamate release, followed by sustained metaplasticity and persisting antidepressant-like effects [3]. Inhibition of the glutamate autoreceptor mGluR2 has also been proposed to enhance the probability of glutamate release, augment glutamatergic transmission, facilitate sustained changes in the capacity for synaptic plasticity, and induce prolonged antidepressant-like effects [212]. 3. Augmentation of glutamatergic receptor activity: Direct activation of NMDARs via positive allosteric modulation promotes enhanced glutamatergic transmission, alters the threshold for LTP formation, and results in enduring antidepressant-like effects. Evidence also suggests sustained metaplasticity and antidepressant effects detected after ketamine administration require NMDAR activation [139]. 4. Increase neurotrophic signaling: Ketamine and numerous metaplasticity-engaging putative ketamine mimetics converge around a mechanism that increases neurotrophic signaling (i.e., BDNF-TrkB-mTORC1), suggesting that targeting antidepressant-relevant metaplastic mechanisms to facilitate neurotrophic factor production may be a viable route for designing novel therapeutics. 5. Enhance or prolong mechanisms underlying the expression or maintenance of potentiated synaptic efficacy: The metaplasticity observed after treatment with ketamine and putative ketamine mimetics alters the duration, direction, or magnitude of synaptic plasticity, suggesting that developing therapeutics that engage metaplastic mechanisms along a pathway that converges with canonical NMDAR activation-dependent LTP to modulate mediators of LTP maintenance is a route that may yield exciting, novel treatment modalities for depression. Abbreviations: AC, adenylyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CaMKII, Ca²⁺-calmodulin-dependent protein kinase II; CaMKII, Ca²⁺-calmodulin-dependent protein kinase IV; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; GABA, γ-aminobutyric acid; GABA_AR, GABA_A receptor; HNK, (2R,6R)-hydroxynorketamine; KET, (R,S)-ketamine; LTP, long-term potentiation; mGluR₂, metabotropic glutamate receptor subtype 2; mTORC1, mechanistic target of rapamycin complex 1; NMDAR, N-methyl-D-aspartate receptor; PKA, protein kinase A; PKC, protein kinase C; TrkB, tropomyosin receptor kinase B. Created with Biorender.com