Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density

David Hottman, Shaowu Cheng, Andrea Gram, Kyle LeBlanc, Li Lian Yuan, Ling Li

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-β deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGTf/fCre+) mice using a Cre/LoxP system under the CAMKIIα promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGTf/fCre+ mice compared with GGTf/fCre− mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGTf/fCre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain.

Original languageEnglish (US)
Pages (from-to)207-217
Number of pages11
JournalNeuroscience
Volume373
DOIs
StatePublished - Mar 1 2018

Bibliographical note

Funding Information:
We thank Dr. Martin Bergo for providing the original breeding pairs for GGT-haplodeficient and GGT floxed mice and Emily Leathley for assistance with electrophysiology experiments. We also thank Drs. Gibson Wood and Mark Distefano for helpful discussions on the data. This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (AG056976 and AG056025), and the College of Pharmacy and the Academic Health Center of the University of Minnesota to LL. DH was supported by an NIH pre-doctoral training fellowship (AG029796) and the Bighley/Rowell Graduate fellowship from the College of Pharmacy at the University of Minnesota.

Funding Information:
We thank Dr. Martin Bergo for providing the original breeding pairs for GGT-haplodeficient and GGT floxed mice and Emily Leathley for assistance with electrophysiology experiments. We also thank Drs. Gibson Wood and Mark Distefano for helpful discussions on the data. This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health ( AG056976 and AG056025 ), and the College of Pharmacy and the Academic Health Center of the University of Minnesota to LL. DH was supported by an NIH pre-doctoral training fellowship ( AG029796 ) and the Bighley/Rowell Graduate fellowship from the College of Pharmacy at the University of Minnesota .

Keywords

  • dendritic spine density
  • geranylgeranyltransferase
  • knockout mouse models
  • protein prenylation
  • small GTPases
  • synaptic plasticity

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