Losing the Beat: Contribution of Purkinje Cell Firing Dysfunction to Disease, and Its Reversal

• Published in: Neuroscience Vol. 462; pp. 247 - 261
• Main Authors: Cook, Anna A., Fields, Eviatar, Watt, Alanna J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 10.05.2021
• Subjects: Action Potentials; Animals; ASD; Ataxia; Autism Spectrum Disorder; Cerebellum; firing; intrinsic activity; Mice; Purkinje cell; Purkinje Cells; CF; AHP; intrinsic activity; MTSS1; cerebellum; 4-AP; SCA; ASD; CV; PC; ataxia; EA2; firing; MF; SFK; GoC; Purkinje cell; HD
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.06.008

[Display omitted] •Purkinje cells are the principle cells of the cerebellum, and fire intrinsically with high frequency and regularity.•A number of diseases converge at least in part on a common functional pathology: Purkinje cell intrinsic firing deficits.•Purkinje cell intrinsic firing deficits typically present peri-onset of behavioral dysfunction, and precede cell loss.•Therapeutic strategies that rescue intrinsic firing deficits often improve behavioral deficits.•Thus we posit that Purkinje cell intrinsic firing deficits is a promising therapeutic target for multiple diseases. The cerebellum is a brain structure that is highly interconnected with other brain regions. There are many contributing factors to cerebellar-related brain disease, such as altered afferent input, local connectivity, and/or cerebellar output. Purkinje cells (PC) are the principle cells of the cerebellar cortex, and fire intrinsically; that is, they fire spontaneous action potentials at high frequencies. This review paper focuses on PC intrinsic firing activity, which is altered in multiple neurological diseases, including ataxia, Huntington Disease (HD) and autism spectrum disorder (ASD). Notably, there are several cases where interventions that restore or rescue PC intrinsic activity also improve impaired behavior in these mouse models of disease. These findings suggest that rescuing PC firing deficits themselves may be sufficient to improve impairment in cerebellar-related behavior in disease. We propose that restoring PC intrinsic firing represents a good target for drug development that might be of therapeutic use for several disorders.