Targeting metaplasticity mechanisms to promote sustained antidepressant actions
Open accessAbstract
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.
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These cascades converge to produce LTP-like synaptic potentiation across corticolimbic circuits within hours, mirroring the temporal profile of ketamine's antidepressant effects.
“These cascades converge to produce long-term potentiation (LTP) like synaptic potentiation across corticolimbic circuits within hours, mirroring the temporal profile of ketamine’s antidepressant effects [20,33,48].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [33]
The sections “Conceptualization of NMDAR inhibitors as rapid-acting antidepressants” and “Future Directions” (pages not provided) describe proposed mechanisms that strengthen excitatory synapses and engage mediators of LTP. The paper also reports rapid synaptic effects and enhanced capacity to form LTP after ketamine, but it does not establish that these cascades produce LTP-like potentiation across corticolimbic circuits within hours or that this follows the same time course as the antidepressant effect. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAcross disease models, TrkB PAMs rescue spine density and preserve mature spine morphology, supporting a model in which TrkB modulation extends antidepressant-like plasticity through sustained structural and proteomic reinforcement.
“Across disease models, TrkB-positive allosteric modulators (PAMs) rescue spine density and preserve mature spine morphology, supporting a model in which TrkB modulation extends antidepressant like plasticity through sustained structural and proteomic reinforcement [33,116,118].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [33]
The ‘Pharmacological direct and indirect NMDAR activators’ section (page unavailable) reports increased mature spine density and sustained antidepressant-like effects with rapastinel, alongside BDNF–TrkB–mTOR signaling. But it identifies rapastinel as an NMDAR PAM, not a TrkB PAM, and does not establish rescue across disease models, preservation of spine morphology, or sustained proteomic reinforcement. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe ICM model assigns each mechanism a temporal role: AMPAR throughput opens the window, TrkB and eEF2K stabilize the rewrite, SV2A protects presynaptic fidelity, and Kv7, HCN, and GIRK channels tune the excitability set point that determines durability.
“Rather than grouping targets by molecular family alone, the ICM model assigns each mechanism a temporal role: AMPAR throughput opens the window, TrkB and eEF2K stabilize the rewrite, SV2A protects presynaptic fidelity, and Kv7, HCN, and GIRK channels tune the excitability set point that determines durability [33,243].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [33]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSynaptic plasticity alone is insufficient for antidepressant response; dynamic regulation of intrinsic excitability acts in parallel to shape circuit output, resilience, and vulnerability.
“Yet synaptic plasticity alone is insufficient. Dynamic regulation of intrinsic excitability, through ion channel dependent control of neuronal gain and firing probability, acts in parallel to shape circuit output, resilience, and vulnerability [32,33].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [33]
The Abstract and the section “Metaplasticity: a druggable mechanism in the context of depression?” describe metaplastic mechanisms that alter subsequent synaptic plasticity and may help sustain antidepressant effects, lending limited support to the point that synaptic changes alone do not tell the whole story. They do not identify dynamic regulation of intrinsic excitability, ion-channel control of neuronal gain or firing probability, or effects on resilience and vulnerability as that parallel mechanism. No page numbers are available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredStress skews synaptic plasticity and intrinsic excitability, degrading cortical and reward circuit function, while rapid-acting and conventional antidepressants restore synaptic strength, spine architecture, and network communication through metaplastic and homeostatic programs that prime future adaptation rather than a single static endpoint.
“Stress skews both, degrading cortical and reward circuit function, while rapid-acting and conventional antidepressants restore synaptic strength, spine architecture, and network communication through metaplastic and homeostatic programs that prime future adaptation rather than a single static endpoint [33,390].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [33]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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References 215 · Cited by 49
Research works printed but not linked: 4
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- Authors
- Brown, K. A., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Molecular Psychiatry
- Published
- 2024-01-04
- Volume
- 29
- Issue
- 4
- Pages
- 1114-1127
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC11176041
- OpenAlex
- W4390579790
- Cited by
- 49
- References
- 215
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 6
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH107615)
- U.S. Department of Veterans Affairs (1I01BX004062, 1I01BX006018)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- metaplasticity, rapid-acting antidepressants, ketamine, esketamine, depression, treatment-resistant depression, NMDA receptor, mGluR2/3, AMPA receptor potentiation, psychedelics, synaptic plasticity, long-term potentiation, glutamatergic synapses, excitatory neurotransmission
- MeSH terms
- Animals, Antidepressive Agents, Depression, Humans, Ketamine, Neuronal Plasticity, Synapses, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation
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