The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

• Published in: Cell reports (Cambridge) Vol. 44; no. 2; p. 115256
• Main Authors: Tolve, Marianna, Tutas, Janine, Özer-Yildiz, Ebru, Klein, Ines, Petzold, Anne, Fritz, Veronika J., Overhoff, Melina, Silverman, Quinn, Koletsou, Ellie, Liebsch, Filip, Schwarz, Guenter, Korotkova, Tatiana, Valtcheva, Silvana, Gatto, Graziana, Kononenko, Natalia L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2025; Elsevier
• Subjects: Adaptor Protein Complex 2 - genetics; Adaptor Protein Complex 2 - metabolism; Animals; AP-2; ataxia; Cerebellum - metabolism; climbing fibers; CP: Neuroscience; Endocytosis; GLURδ2; Glutamic Acid - metabolism; GRID2IP; Mice; Mice, Inbred C57BL; neurodegeneration; parallel fibers; Purkinje cell; Purkinje Cells - metabolism; Receptors, Glutamate - metabolism; Synapses - metabolism; parallel fibers; ataxia; CP: Neuroscience; neurodegeneration; AP-2; Purkinje cell; climbing fibers; GRID2IP; GLURδ2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115256

The loss of cerebellar Purkinje cells is a hallmark of neurodegenerative movement disorders, but the mechanisms remain enigmatic. We show that endocytic adaptor protein complex 2 (AP-2) is crucial for Purkinje cell survival. Using mouse genetics, viral tracing, calcium imaging, and kinematic analysis, we demonstrate that loss of the AP-2 μ subunit in Purkinje cells leads to early-onset ataxia and progressive degeneration. Synaptic dysfunction, marked by an overrepresentation of parallel fibers (PFs) over climbing fibers (CFs), precedes Purkinje cell loss. Mechanistically, AP-2 interacts with the PF-enriched protein GRID2IP, and its loss triggers GRID2IP degradation and glutamate δ2 receptor (GLURδ2) accumulation, leading to an excess of PFs while CFs are reduced. The overrepresentation of PFs increases Purkinje cell network activity, which is mitigated by enhancing glutamate clearance with ceftriaxone. These findings highlight the role of AP-2 in regulating GRID2IP levels in Purkinje cells to maintain PF-CF synaptic balance and prevent motor dysfunction. [Display omitted] •Endocytic adaptor AP-2 is a crucial regulator of synaptic connectivity in the cerebellum•Loss of AP-2 in Purkinje cells disrupts GRID2IP stability and GLURδ2 localization•AP-2 deletion causes excess PF synapses and a drastic reduction in CF synapses•AP-2 dysfunction alters cerebellar network, drives neurodegeneration, and causes ataxia Tolve et al. demonstrate that AP-2 stabilizes GRID2IP to regulate synaptic function in Purkinje cells. Loss of AP-2 disrupts synaptic connectivity, alters network activity, and impacts motor coordination. This study highlights the importance of AP-2 in cerebellar function and its implications for neurodegenerative disorders.