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Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala

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Abstract

Tambaleante (tbl/tbl) is a mutant mouse that carries a spontaneous Gly483Glu substitution in the HERC1 (HECT domain and RCC1 domain) E3 ubiquitin ligase protein (HERC1). The tbl/tbl mutant suffers an ataxic syndrome given the almost complete loss of cerebellar Purkinje cells during adult life. More recent analyses have identified alterations at neuromuscular junctions in these mice, as well as in other neurons of the central nervous system, such as motor neurons in the spinal cord, or pyramidal neurons in the hippocampal CA3 region and the neocortex. Accordingly, the effect of the tbl/tbl mutation apparently extends to other regions of the nervous system far from the cerebellum. As HERC1 mutations in humans have been correlated with intellectual impairment, we studied the effect of the tbl/tbl mutation on learning. Using a behavioral test, ex vivo electrophysiological recordings, immunohistochemistry, and Golgi method, we analyzed the associative learning in the lateral amygdala of the tbl/tbl mouse. The tbl/tbl mice perform worse than wild-type animals in the passive avoidance test, and histologically, the tbl/tbl mice have more immature forms of dendritic spines. In addition, LTP cannot be detected in these animals and their STP is dampened, as is their glutamatergic input to the lateral amygdala. Together, these data suggest that HERC1 is probably involved in regulating synaptic function in the amygdala. Indeed, these results indicate that the tbl/tbl mutation is a good model to analyze the effect of alterations to the ubiquitin–proteasome pathway on the synaptic mechanisms involved in learning and its defects.

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Acknowledgements

We are indebted to A. Gruart (anti-VGLUT1, anti-ChAT), S. Martinez (anti-GluA1R), and L. Tabares (anti-SV2A) for their generous gift of the antibodies used. Similarly, we are indebted to L. Tabares and G. Alvarez de Toledo for the facilities to use the Olympus FluoView 1000 laser confocal scanning microscope. The technical assistance of F.J. García-Reyes and Laura Raposo is also greatly appreciated. We are also indebted to J.L. Rosa for the generous gift of the tbl/tbl founder mice. We acknowledge the assistance of Dr. M. Sefton in the preparation of this manuscript. This work received financial support from the following grants: EM P-V (DGICYT BFU2011-27207 and Spanish Junta de Andalucía CTS-2257); JV N-D (CONACYT postdoctoral scholarship); RR (Juan de la Cierva contract JCI-2011-08888 from the MINECO, and VPPI-US from the University of Seville); AMC (Fundación Ramón Areces, DGICYT BFU2011-27207, and the Junta de Andalucía CTS-2257); AR-M (MINECO/FEDER BFU2012-38208 and the Junta de Andalucía P11-CVI-7290); and JAA (Spanish Junta de Andalucía BIO-122 and DGICYT BFU2015-64536-R).

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Authors and Affiliations

  1. Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Ctra Utrera km. 1, 41013, Seville, Spain

    Eva Mª Pérez-Villegas, José V. Negrete-Díaz, Mª Elena Porras-García, Angel M. Carrión, Antonio Rodríguez-Moreno & José A. Armengol

  2. División de Ciencias de la Salud e Ingenierías, Universidad de Guanajuato, Campus Celaya-Salvatierra, Guanajuato, Mexico

    José V. Negrete-Díaz

  3. Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, 41012, Seville, Spain

    Rocío Ruiz

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  1. Eva Mª Pérez-Villegas
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  2. José V. Negrete-Díaz
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  3. Mª Elena Porras-García
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  4. Rocío Ruiz
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  5. Angel M. Carrión
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  6. Antonio Rodríguez-Moreno
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  7. José A. Armengol
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Correspondence to José A. Armengol.

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Eva Mª Pérez-Villegas, José V. Negrete-Díaz, and Mª Elena Porras-García contributed equally to this work

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Pérez-Villegas, E.M., Negrete-Díaz, J.V., Porras-García, M.E. et al. Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala. Mol Neurobiol 55, 1157–1168 (2018). https://doi.org/10.1007/s12035-016-0371-8

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