Objective: To develop a mouse model of chronic corticostriatal overactivity and increase expression of corticostriatal alpha-synuclein.

Background: Parkinson’s disease typically has a focal motor onset¹, which contrasts with the absence of somatotopic organization in the degenerating substantia nigra pars compacta². To solve this paradox, we recently proposed a cortical pathogenic theory of Parkinson’s disease, suggesting that corticostriatal overactivity might act as a top-down somatotopic stressor for nigrostriatal dopaminergic terminals via a mechanism mediated by activity-dependent secretion of alpha-synuclein at corticostriatal terminals³. An animal model to test our cortical pathogenic theory of Parkinson’s disease is currently lacking.

Method: We developed a combined viral vector strategy to transfect glutamatergic corticostriatal neurons in the primary motor cortex of wild-type mice with adenoviruses expressing Designer Receptors Exclusively Activated by Designer Drug (DREADDs) and human alpha-synuclein. We used in vivo extracellular electrophysiology to test the ability to chemogenetically increase corticostriatal activity, and post-mortem immunohistochemistry to assess viral transfection and protein expression.

Results: The electrophysiological experiments showed that systemic administration of clozapine N-oxide (CNO) could tonically increase for hours the firing rate of the targeted layer V corticostriatal neurons in the motor cortex. We also established the feasibility of chronic administration of CNO (daily subcutaneous injections) for at least 4 weeks. The immunohistochemistry displayed robust expression of human alpha-synuclein and co-expression of DREADDs in the corticostriatal projection. Chronically increasing corticostriatal activity alone (i.e. without over-expressing alpha-synuclein) was not sufficient to initiate nigrostriatal degeneration nor to induce a robust inflammatory response at striatal level, establishing the baseline control condition for alpha-synuclein-dependent manipulations.

Conclusion: We obtained a viable mouse model of chronic corticostriatal overactivity and increased expression of corticostriatal alpha-synuclein that can be used to causally test our cortical pathogenic theory of Parkinson’s disease.

References: 1. Monje MHG, Sánchez-Ferro A, Pineda Pardo JA, Vela-Desojo L, Alonso-Frech F, Obeso JA. Motor onset topography and progression in Parkinson’s disease: the upper limb is first. Mov Disord 2021; 36:905-915
2. Nambu A. Somatotopic organization of the primate Basal Ganglia. Front Neuroanat 2011; 5: 26
3. Foffani G, Obeso JA. A cortical pathogenic theory of Parkinson’s disease. Neuron 2018; 99: 1116-1128

« Back to 2022 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/a-mouse-model-to-test-the-cortical-pathogenic-theory-of-parkinsons-disease/