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Neuronal Protein Farnesylation Regulates Hippocampal Synaptic Plasticity and Cognitive Function

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Abstract

Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Two enzymes, farnesyltransferase (FT) and geranylgeranyltransferase type I (GGT), are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of Alzheimer’s disease. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in shaping neuronal functions and cognition remains elusive. This study shows that in contrast to the detrimental effects of GGT reduction, systemic haplodeficiency of FT has little to no impact on hippocampal synaptic plasticity and cognition. However, forebrain neuron-specific FT deletion also leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Furthermore, a novel prenylomic analysis identifies distinct pools of prenylated proteins that are affected in the brain of forebrain neuron-specific FT and GGT knockout mice, respectively. Taken together, this study uncovers that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions.

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Acknowledgments

We thank Dr. Martin Bergo for providing the original breeding pairs for FT- and GGT-haplodeficient and floxed mice and Andrea Gram for maintaining and genotyping different lines of experimental mice.

Funding

This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (AG056976 and AG058081), National Institute of General Medical Science (R01GM084152), the National Institute of Neurological Disorders and Stroke (R01NS107442), and the National Science Foundation (CHE-1308655). KFS was supported by a Doctoral Dissertation Fellowship from the University of Minnesota.

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Authors and Affiliations

  1. Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Wenhui Qu & Ling Li

  2. Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA

    Kiall F. Suazo & Mark D. Distefano

  3. Department of Experimental and Clinical Pharmacology, University of Minnesota, McGuire Translational Research Facility (MTRF) 4-208, 2001 6th Street SE, Minneapolis, MN, 55455, USA

    Wenfeng Liu, Shaowu Cheng, Angela Jeong, David Hottman & Ling Li

  4. Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA, 50312, USA

    Li-Lian Yuan

  5. Graduate Program in Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA

    Ling Li

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  1. Wenhui Qu
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  9. Ling Li
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Contributions

WQ performed electrophysiological experiments, behavioral assays for the FT+/- mice and their controls, analyzed the data, interpreted the results, and wrote the manuscript. KS performed prenylomic analysis and wrote the manuscript. WL conducted Golgi staining and quantification of dendritic spine density. SC performed behavioral assays for the FTf/fCre+ and FTf/fCre− mice. DH assisted with electrophysiological and Golgi staining experiments. AJ processed samples for the prenylomic analysis and provided suggestions on the manuscript. MD designed and supervised the prenylomic part of the study. LY contributed to the discussion and interpretation of the data from electrophysiological experiments. LL conceived the study, supervised the progress of all experiments, interpreted the results, and edited and finalized the manuscript

Corresponding author

Correspondence to Ling Li.

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All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Minnesota.

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Qu, W., Suazo, K.F., Liu, W. et al. Neuronal Protein Farnesylation Regulates Hippocampal Synaptic Plasticity and Cognitive Function. Mol Neurobiol 58, 1128–1144 (2021). https://doi.org/10.1007/s12035-020-02169-w

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