Key Takeaways & Executive Findings
- •• Celsr3 knockout in Purkinje cells causes ataxia-like behavior and synaptic deficits, including impaired mEPSCs and LTP. • Forskolin, a cAMP activator, ameliorates ataxia-like behavior and restores synaptic function in Celsr3 cKO mice. • The therapeutic effects of forskolin are mediated via the cAMP/Epac pathway, not PKA, as shown by antagonist studies. • Forskolin represents a potential therapeutic agent for inherited cerebellar ataxias involving synaptic dysfunction.
Abstract
AIM: To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout (cKO) mice. METHODS: The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests, and the molecular mechanisms were investigated by patch-clamp experiments. RESULTS: The loss of Celsr3 led to ataxia-like behavior, accompanied by impaired miniature excitatory postsynaptic currents (mEPSCs) and postsynaptic long-term potentiation (LTP) in PCs. The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice. Interestingly, the effects of forskolin could be blocked by SQ22536 (a cAMP antagonist) and ESI-08 (exchange protein activated by cAMP antagonist; Epac) but the H89 (a PKA antagonist) could not block the effects. CONCLUSION: Celsr3 plays an important role in motor coordination by modulating synaptic function, and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
1. Introduction
Although locomotion is an essential part of life, the mechanisms underlying the modulation of locomotory behavior are still unclear. Motor behavior and learning are complex and precise processes that are mediated by particular neural circuits and synaptic plasticity [1-2]. The cerebellum is primarily responsible for controlling motor behavior, especially whole-body locomotion, which we define here as coordinated movement involving the whole body (including the head, back, and extremities) along a defined spatial trajectory [3]. Cerebral dysfunction can cause a series of unique symptoms that are clinically defined as ataxia.
The Purkinje cells (PCs) in the cerebellum are the central component of the cerebellar circuit and are critical for modulating motor coordination, balance, posture, and skill-based learning [4-6]. PCs receive excitatory glutamatergic inputs mainly from the parallel fibers (PFs) that extend from granule cells [7]. LTP disruption in cerebellar PF-PC synapses is considered the key pathological factor in cerebellar ataxia [8], but how motor function is mediated by LTP is still unclear. In our previous study, we reported that conditional knockout (cKO) of Celsr3 in PCs impaired miniature excitatory postsynaptic currents (mEPSCs) and LTP in PF-PC synapses and that Celsr3 cKO mice presented symptoms such as ataxia and impaired motor learning. Interestingly, forskolin directly induced LTP in the PF-PC synapses of cKO mice [9], indicating that forskolin could modulate LTP-mediated behavior.
Forskolin is a labdane-type diterpenoid that has considerable anticancer, antiasthmatic, antihypertensive, and cardiac strengthening effects [10]. In our previous study, we reported that forskolin could restore the function of PCs in mice with conditional knockout of an atypical cadherin receptor (Celsr3) [9], but the effect of forskolin on ataxia has not been well explored. Here, therefore, we explored this effect and identified the potential functions of forskolin in ataxia.
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WU Chuyue, GUO Jing, HONG Tu, HUANG Yu, CHEN Shengli, ZHOU Qinji (2026). Forskolin ameliorates ataxia-like behavior in Purkinje cell-Celsr3 cKO mice via cAMP/Epac signaling pathway. Chinese Journal of Pathophysiology. https://doi.org/10.3969/j.issn.1000-4718.2025.12.001
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Frequently Asked Questions
What is the role of Celsr3 in motor coordination?
Celsr3 plays an important role in motor coordination by modulating synaptic function in Purkinje cells. Its loss leads to ataxia-like behavior and impaired synaptic plasticity, including reduced mEPSCs and LTP.
How does forskolin improve ataxia-like behavior in Celsr3 cKO mice?
Forskolin, a cAMP activator, ameliorates ataxia-like behavior by restoring synaptic function, specifically by rescuing mEPSCs and LTP impairments in Purkinje cells. Its effects are mediated via the cAMP/Epac signaling pathway, not PKA.
What is the significance of the cAMP/Epac pathway in this study?
The study demonstrates that forskolin's beneficial effects are mediated through the cAMP/Epac pathway, as blocking Epac with ESI-08 abolished the effects, while blocking PKA with H89 did not. This identifies a specific molecular target for potential therapeutic intervention.
Could forskolin be a potential treatment for inherited cerebellar ataxia?
Yes, the findings suggest that forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia, particularly those involving synaptic dysfunction in Purkinje cells.
What experimental methods were used in this study?
The study used behavioral tests to evaluate motor function, patch-clamp experiments to measure synaptic currents and plasticity, and pharmacological antagonists to dissect signaling pathways. Genetically modified mice with Celsr3 conditional knockout in Purkinje cells were employed.
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