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Proteolytic Degradation of Hippocampal STEP61 in LTP and Learning

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Abstract

Striatal-enriched protein tyrosine phosphatase (STEP) modulates key signaling molecules involved in synaptic plasticity and neuronal function. It is postulated that STEP opposes the development of long-term potentiation (LTP) and that it exerts a restraint on long-term memory (LTM). Here, we examined whether STEP61 levels are regulated during hippocampal LTP and after training in hippocampal-dependent tasks. We found that after inducing LTP by high frequency stimulation or theta-burst stimulation STEP61 levels were significantly reduced, with a concomitant increase of STEP33 levels, a product of calpain cleavage. Importantly, inhibition of STEP with TC-2153 improved LTP in hippocampal slices. Moreover, we observed that after training in the passive avoidance and the T-maze spontaneous alternation task, hippocampal STEP61 levels were significantly reduced, but STEP33 levels were unchanged. Yet, hippocampal BDNF content and TrkB levels were increased in trained mice, and it is known that BDNF promotes STEP degradation through the proteasome. Accordingly, hippocampal pTrkBTyr816, pPLCγTyr783, and protein ubiquitination levels were increased in T-SAT trained mice. Remarkably, injection of the TrkB antagonist ANA-12 (2 mg/Kg, but not 0.5 mg/Kg) elicited LTM deficits and promoted STEP61 accumulation in the hippocampus. Also, STEP knockout mice outperformed wild-type animals in an age- and test-dependent manner. Summarizing, STEP61 undergoes proteolytic degradation in conditions leading to synaptic strengthening and memory formation, thus highlighting its role as a molecular constrain, which is removed to enable the activation of pathways important for plasticity processes.

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Acknowledgments

The authors are very grateful to A. López and M. T. Muñoz for their technical support, and to Dr. Paul J. Lombroso (Child Study Center, Yale School of Medicine, Yale University, New Haven, CT, USA) for providing the STEP KO mice to establish our colony, and the STEP inhibitor TC-2153.

Funding

This work was supported by the Ministerio de Economia y Competitividad, Spain (SAF2016-08573-R to E. Pérez-Navarro and BFU2014-57929-P, cofinanced by FEDER, to E.D. Martín).

Author information

Author notes

  1. Jesús J. Ballesteros

    Present address: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

  2. Jesús J. Ballesteros

    Present address: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

  3. Shiraz Tyebji

    Present address: Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia

  4. Sara Martínez-Torres

    Present address: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain

  5. Rosa López-Hidalgo

    Present address: Grupo de Patología Celular y Molecular del Alcohol, Centro de Investigación Príncipe Felipe, Valencia, Spain

  6. Eduardo D. Martín

    Present address: Instituto Cajal, CSIC, Madrid, Spain

  7. Jesús J. Ballesteros and Shiraz Tyebji contributed equally to this work.

Authors and Affiliations

  1. Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, C/ Casanova, 143 08036, Barcelona, Catalonia, Spain

    Ana Saavedra, Shiraz Tyebji, Sara Martínez-Torres, Gloria Blázquez, Garikoitz Azkona, Jordi Alberch & Esther Pérez-Navarro

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

    Ana Saavedra, Shiraz Tyebji, Gloria Blázquez, Garikoitz Azkona, Jordi Alberch & Esther Pérez-Navarro

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Ana Saavedra, Shiraz Tyebji, Gloria Blázquez, Garikoitz Azkona, Jordi Alberch & Esther Pérez-Navarro

  4. Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Albacete, Spain

    Jesús J. Ballesteros, Rosa López-Hidalgo & Eduardo D. Martín

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  1. Ana Saavedra
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  9. Eduardo D. Martín
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Correspondence to Esther Pérez-Navarro.

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Electronic Supplementary Material

Fig. S1

Relative abundance of STEP61 and STEP33 in hippocampal extracts. Representative immunoblot for STEP61 and STEP33 from the same film exposition showing that to detect the 33 kDa band the 61 kDa isoform becomes overexposed. (PDF 39.4 kb)

Fig. S2

Similar STEP61 ubiquitination patterns after immunoprecipitation (IP) of STEP from native or denatured samples. STEP was immunoprecipitated from native (STEPn) or denatured (STEPdn) hippocampal extracts and Western blot (WB) was performed against ubiquitin and STEP. A mouse IgG was used as control. p, pellet; sp, supernatant. (PDF 47 kb)

Fig. S3

No changes in STEP61 levels in the hippocampus earlier than 1 h post-training in the T-SAT. Hippocampal STEP61 levels were analyzed by Western blot of protein extracts obtained from the hippocampus of naïve mice, and mice trained in the T-SAT and sacrificed 15 or 30 min later. Representative immunoblots are shown. Values (obtained by densitometric analysis of Western blot data) are expressed as percentage of naïve mice and shown as mean ± SEM (n = 4-7). (PDF 41.1 kb)

Fig. S4

Injection of 0.5 mg/Kg ANA-12 has no effect on LTM in the T-SAT or on hippocampal STEP61 levels. a Mice received an intraperitoneal injection of saline or 0.5 mg/Kg ANA-12 and were trained in the T-SAT immediately after. LTM was assessed 4 h later. The graph shows the percentage of arm preference (mean ± SEM; n = 13/group). Data were analyzed by Student’s t test. ***P < 0.001 as compared to old arm. b STEP61 levels were analyzed by Western blot of protein extracts obtained from the hippocampus of mice injected with saline or 0.5 mg/Kg ANA-12 before T-SAT training and subjected to LTM assessment. Representative immunoblots are shown. Values (obtained by densitometric analysis of Western blot data) are expressed as percentage of saline-treated mice and shown as mean ± SEM (n = 6/group). Data were analyzed by Student’s t test. (PDF 17.1 kb)

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Saavedra, A., Ballesteros, J.J., Tyebji, S. et al. Proteolytic Degradation of Hippocampal STEP61 in LTP and Learning. Mol Neurobiol 56, 1475–1487 (2019). https://doi.org/10.1007/s12035-018-1170-1

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  • DOI: https://doi.org/10.1007/s12035-018-1170-1

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