In recent decades, electroconvulsive therapy (ECT) has re-emerged as a potent clinical intervention for treatment-resistant depression, gradually dispelling earlier stigmas attached to its use. The therapeutic efficacy of ECT, however, remains not fully understood at the mechanistic level, prompting neuroscientists to utilize animal models to simulate clinical conditions and elucidate molecular, cellular, and systemic pathways involved in its antidepressant effects. A groundbreaking systematic review published in Translational Psychiatry in 2025, led by Kokolakis and colleagues, consolidates the current landscape of in vivo rodent ECT models, furnishing invaluable insight into their translational relevance for depression research.
Rodents, primarily mice and rats, have long served as quintessential subjects in neuroscience due to their well-characterized neuroanatomy and genetics, alongside their behavioral responsiveness to stress and psychotropic interventions. The reviewed article meticulously surveys experimental paradigms that administer electroconvulsive shocks to rodents to mimic key features of human ECT. These models aim to recapitulate the therapeutic seizure activity elicited in patients, thereby exploring the neurobiological sequelae underpinning antidepressant responses. A careful analysis reveals the nuances in stimulus parameters—voltage, current duration, and frequency—tailored to optimize validity while minimizing adverse effects inherent to animal research.
Upon application of ECT in rodent models, researchers observe a fascinating cascade of neurochemical and electrophysiological alterations within critical brain regions involved in mood regulation, including the hippocampus, prefrontal cortex, and amygdala. The review highlights consistent findings such as enhanced neurogenesis, upregulated expression of brain-derived neurotrophic factor (BDNF), and modulation of neurotransmitter systems encompassing serotonin, dopamine, and glutamate circuits. These biological shifts mirror clinical observations in human cohorts, underscoring the translational fidelity of these animal systems.
Intriguingly, the review delineates how repeated ECT sessions induce sustained synaptic plasticity and structural remodeling. Dendritic spine density augmentation and augmented synaptic efficacy documented in rodent hippocampal neurons suggest that ECT facilitates the brain’s intrinsic capacity for repair and adaptation. These synaptic changes are posited to counteract the synaptic deficits characteristically observed in depressive phenotypes. Furthermore, genetic models combined with ECT exposure offer a platform to dissect causal links between specific molecular pathways and behavioral outcomes.
The systematic evaluation underscores the importance of standardized protocols while acknowledging variations across laboratories that affect reproducibility. Parameters such as electrode placement and seizure threshold determination critically influence both the induction of seizures and downstream neurobiological effects. Refinements in sedation and anesthesia techniques concurrently improve animal welfare without compromising the robustness of seizure induction, thereby addressing ethical dimensions of in vivo ECT experiments.
One of the pivotal discussions revolves around behavioral assays employed to evaluate antidepressant-like effects post-ECT. Tests like the forced swim test, sucrose preference test, and novelty-suppressed feeding are universally utilized to quantify despair-like behavior and anhedonia in rodents. The authors stress that improved behavioral outcomes correlate with neuroplastic changes, offering a multi-dimensional framework to probe the efficacy and mechanism of ECT beyond electrophysiological metrics.
Importantly, the review underscores unresolved questions about the heterogeneity in response to ECT, both in clinical subjects and rodent populations. Genetic backgrounds, age, sex, and comorbid conditions contribute to varied outcomes, necessitating refined experimental designs that embrace this biological complexity. Future endeavors integrating multi-omics approaches and longitudinal imaging promise to unravel how individual differences shape the trajectory of ECT efficacy.
In addition to classical neurotrophin and neurotransmitter paradigms, the paper draws attention to emerging avenues linking neuroinflammation and immune signaling with the therapeutic actions of ECT. Rodent models reveal downregulation of proinflammatory cytokines and enhancement of anti-inflammatory pathways post-treatment, implying a multifactorial neuroimmune interplay. Such insights enrich conceptual frameworks that extend beyond monoaminergic theories dominating depression research.
Technological advancements also feature prominently in the review, highlighting innovations such as closed-loop ECT systems enabling precise seizure induction synchronized with real-time neurophysiological monitoring. These cutting-edge models facilitate exploration of seizure dynamics and their immediate network-level consequences. Combined with optogenetic and chemogenetic methods, researchers now possess unprecedented tools to probe circuitry-level adaptations induced by ECT.
The authors advocate for rigorous cross-species translational studies that align rodent models with human brain imaging and electrophysiological data. This integrative strategy promises to refine biomarkers predictive of ECT response, optimizing personalized treatment regimens. Moreover, preclinical models serve as testbeds to evaluate novel ECT variants, such as magnetic seizure therapy, potentially offering improved side effect profiles alongside robust antidepressant efficacy.
Overall, this comprehensive synthesis by Kokolakis et al. renders an essential resource for neuroscience and psychiatry communities engaged in experimental therapeutics. The convergence of robust in vivo data with translational imperatives heralds a new era in depression research grounded in mechanistic clarity and clinical relevance. As mental health crises escalate globally, these foundational insights catalyze more refined and humane interventional strategies combating refractory depression.
The rigorous systematic approach inherent in this review identifies critical gaps including the need for longitudinal studies tracking durable neuroplastic changes and cognitive outcomes post-ECT. It calls for better alignment of electrophysiological parameters with behavioral endpoints to isolate mechanisms driving both efficacy and side effects. Enhanced reporting standards and collaborative networks among preclinical researchers stand as vital steps forward.
In the grand schema, rodent ECT models embody powerful experimental platforms bridging bench to bedside with potential to unravel the enigmatic biological underpinnings of electroconvulsive therapies. The field advances toward a future where improved understanding not only demystifies ECT but also informs next-generation neuromodulatory interventions offering rapid, robust, and durable relief for individuals battling major depressive disorders.
This carefully curated synthesis extends beyond a mere catalog of studies; it frames a dynamic narrative emphasizing the synergy between innovative rodent modeling and translational psychiatry. As neuropsychiatric research surges toward precision medicine, such integrative reviews chart transformative pathways illuminating how ancient therapies like ECT adapt to modern scientific scrutiny and clinical demands.
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Subject of Research:
In vivo rodent models of electroconvulsive therapy (ECT) applied to translational depression research.
Article Title:
Contemporary in vivo rodent electroconvulsive therapy (ECT) models in translational depression research: a systematic review.
Article References:
Kokolakis, E., Gottschalk, M.G., Kläffgen, S. et al. Contemporary in vivo rodent electroconvulsive therapy (ECT) models in translational depression research: a systematic review. Transl Psychiatry (2025). https://doi.org/10.1038/s41398-025-03749-x
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