Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories

Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories

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J Psychiatry Neurosci 2014;39(4):259-66

Liangli Wang, PhD; Ramona M. Rodriguiz, PhD; William C. Wetsel, PhD; Huaxin Sheng, MD; Shengli Zhao, PhD; Xiaozhi Liu, MS; Wulf Paschen, PhD; Wei Yang, PhD

Wang, Sheng, Liu, Paschen, Yang — Department of Anesthesiology, Duke University, Durham, NC; Rodriguiz, Wetsel — Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University, Durham, NC; Wetsel — Departments of Psychiatry and Behavioral Sciences, and Cell Biology, Duke University, Durham, NC; Wetsel, Zhao — Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

Abstract

Background: Growing evidence suggests that small ubiquitin-like modifier (SUMO) conjugation plays a key role in brain plasticity by modulating activity-dependent synaptic transmission. However, these observations are based largely on cell culture experiments. We hypothesized that episodic and fear memories would be affected by silencing SUMO1–3 expression.

Methods: To investigate the role of SUMO conjugation in neuronal functioning in vivo, we generated a novel Sumo transgenic mouse model in which a Thy1 promoter drives expression of 3 distinct microRNAs to silence Sumo1–3 expression, specifically in neurons. Wild-type and Sumo1–3 knockdown mice were subjected to a battery of behavioural tests to elucidate whether Sumoylation is involved in episodic and emotional memory.

Results: Expression of Sumo1–3 microRNAs and the corresponding silencing of Sumo expression were particularly pronounced in hippocampal, amygdala and layer V cerebral cortex neurons. The Sumo knockdown mice displayed anxiety-like responses and were impaired in episodic memory processes, contextual and cued fear conditioning and fear-potentiated startle.

Limitations: Since expression of Sumo1–3 was silenced in this mouse model, we need to verify in future studies which of the SUMO paralogues play the pivotal role in episodic and emotional memory.

Conclusion: Our results indicate that a functional SUMO conjugation pathway is essential for emotionality and cognition. This novel Sumo knockdown mouse model and the technology used in generating this mutant may help to reveal novel mechanisms that under lie a variety of neuropsychiatric conditions associated with anxiety and impairment of episodic and emotional memory.


Submitted July 22, 2013; Revised Nov. 15, Dec. 22, 2013, Jan. 4, 2014; Accepted Jan. 6, 2014.

Acknowledgements: The authors thank Kathy Gage, research development associate, for her excellent editorial contribution in the preparation of this manuscript, Pei Miao for her excellent technical assistance, and Dr. Michael J. Matunis for providing the Sumo1 antibody. Some of the experiments were conducted with equipment and software purchased with a grant from North Carolina Biotechnology Center. This study was supported by funds from the Department of Anesthesiology and the Mouse Behavioural and Neuroendocrine Analysis Core Facility, Duke University Medical Center, by NIH R01 grants HL095552 and NS081299 (to W.P.), and by AHA scientist development grant 12SDG11950003 (to W.Y.).

Competing interests: None declared.

Contributors: W.C. Wetsel, S. Zhao, W. Paschen and W. Yang designed the study. L. Wang, R.M. Rodriguiz, W.C. Wetsel, H. Sheng, X. Liu and W. Paschen acquired the data, which L. Wang, R.M. Rodriguiz, W.C.Wetsel, W. Paschen and W. Yang analyzed. R.M. Rodriguiz, W.C.Wetsel, W. Paschen and W. Yang wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.130148

Correspondence to: W. Paschen or W. Yang, Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, 130 + 152 Sands Building, Research Dr., Durham, NC 27710, USA; wulf.paschen@duke.edu or wei.yang@duke.edu