AMPAR Auxiliary Protein SHISA6 Facilitates Purkinje Cell Synaptic Excitability and Procedural Memory Formation

• Published in: Cell reports (Cambridge) 2020-04, Vol.31 (2), p.107515-107515, Article 107515
• Main Authors: Peter, Saša, Urbanus, Bastiaan H.A., Klaassen, Remco V., Wu, Bin, Boele, Henk-Jan, Azizi, Sameha, Slotman, Johan A., Houtsmuller, Adriaan B., Schonewille, Martijn, Hoebeek, Freek E., Spijker, Sabine, Smit, August B., De Zeeuw, Chris I.
• Format: Article
• Language: English
• Subjects: AMPAR kinetics; Animals; auxiliary subunit; Carrier Proteins - genetics; Carrier Proteins - metabolism; cerebellum; Excitatory Postsynaptic Potentials - physiology; Female; Glutamic Acid - metabolism; long-term depression; Long-Term Potentiation - physiology; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - metabolism; procedural memory; Protein Transport; Purkinje Cells - metabolism; Receptors, AMPA - metabolism; synapse; Synapses - metabolism; Synaptic Transmission - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.03.079

The majority of excitatory postsynaptic currents in the brain are gated through AMPA-type glutamate receptors, the kinetics and trafficking of which can be modulated by auxiliary proteins. It remains to be elucidated whether and how auxiliary proteins can modulate synaptic function to contribute to procedural memory formation. In this study, we report that the AMPA-type glutamate receptor (AMPAR) auxiliary protein SHISA6 (CKAMP52) is expressed in cerebellar Purkinje cells, where it co-localizes with GluA2-containing AMPARs. The absence of SHISA6 in Purkinje cells results in severe impairments in the adaptation of the vestibulo-ocular reflex and eyeblink conditioning. The physiological abnormalities include decreased presence of AMPARs in synaptosomes, impaired excitatory transmission, increased deactivation of AMPA receptors, and reduced induction of long-term potentiation at Purkinje cell synapses. Our data indicate that Purkinje cells require SHISA6-dependent modification of AMPAR function in order to facilitate cerebellar, procedural memory formation. [Display omitted] •SHISA6 is prominently expressed in Purkinje cells in close association with AMPARs•SHISA6 absence in Purkinje cells results in impaired procedural memory formation•Purkinje cell synaptic baseline excitatory transmission is facilitated by SHISA6•Purkinje cell AMPAR kinetics are modulated by SHISA6 Peter et al. show that the SHISA6 protein modulates the synaptic function of Purkinje cells in mice. In the absence of SHISA6, memory formation during classical eyeblink conditioning and eye movement adaptations is severely impaired as a result of a major synaptic excitability phenotype in Purkinje cells.