Objective: To define the motor and non-motor phenotypic features of a novel Adcy5^R419W mouse line [1] and validate it as an integrated model of human mixed movement disorders linked to ACDY5 (MxMD-ADCY5) [2]

Background: In humans, the ADCY5 R418W variant leads to severe hyperkinetic movements with orofacial and psychiatric symptoms [3]. This gain-of-function mutation increases adenylyl cyclase 5 activity [4], resulting in altered cAMP signaling within striatal projection neurons in the direct and indirect pathways. The resulting imbalance is hypothesized to drive the hyperkinetic movements, and the most promising therapeutic option is modulation of adenosine and/or dopamine signaling [1,2,5].

A knock-in mouse model with the corresponding Adcy5 R419W mutation was generated. Preliminary phenotypic examination of heterozygous (HET) and homozygous (HOM) mice revealed significant motor impairments (rotarod, notched beam test) compared with wild-type (WT). Notched beam crossing was specifically rescued by modulation of adenosine receptors.

Method: We performed additional behavioral tests to evaluate balance and gait under low-stress conditions (ledge test) and orofacial skills (Capellini test), as well as non-motor phenotypes (novel object recognition (NOR) test). We hypothesized that these mice would present further motor deficits and an anxiety-like phenotype.

Results: HOM mice had difficulty moving on the ledge compared with WT and HET mice, confirming motor impairment. These mice also ate fewer pasta and showed atypical eating strategies in the capellini test, suggesting orofacial difficulties. HOM mice spent more time investigating objects during the NOR test, suggesting hypersensitivity to novelty. HOM mice spent more time in the center of the NOR open-field, supporting anxiety-like behavior.

Conclusion: We demonstrated that Adcy5^R419W mice have motor impairment, including orofacial movements. They also show a composite non-motor phenotype with cognitive and affective components. These results validate this mouse model which will allow a better understanding of a broad group of dyskinesias involving striatal cAMP signaling pathways. Ongoing behavioral investigations will refine this phenotypic characterization and pharmacological rescue experiments will explore potential therapeutic strategies.

References: [1] Yuan R, Roze E, Doulazmi M, et al. Modulation of striatal cAMP levels: A key pathway in the treatment of hyperkinetic movement disorders. iScience. 2026;29(2):114457. doi:10.1016/j.isci.2025.114457

[2] Menon PJ, Nilles C, Silveira‐Moriyama L, et al. Scoping Review on ADCY5 ‐Related Movement Disorders. Movement Disord Clin Pract. 2023;10(7):1048-1059. doi:10.1002/mdc3.13796

[3] Méneret A, Tarrano C, Ekmen A, et al. Psychiatric Disorders and Apathy in Mixed Movement Disorders Linked to ADCY5 ( MXMD ‐ ADCY5 ) . Movement Disorders. Published online January 30, 2026:mds.70208. doi:10.1002/mds.70208

[4] Doyle TB, Hayes MP, Chen DH, Raskind WH, Watts VJ. Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia. Biochemical Pharmacology. 2019;163:169-177. doi:10.1016/j.bcp.2019.02.005

[5] Méneret A, Mohammad SS, Cif L, et al. Efficacy of Caffeine in ADCY5 ‐Related Dyskinesia: A Retrospective Study. Movement Disorders. 2022;37(6):1294-1298. doi:10.1002/mds.29006

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MDS Abstracts - https://www.mdsabstracts.org/abstract/behavioral-phenotype-of-a-mouse-model-of-mixed-movement-disorders-linked-to-adcy5/