Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

Andre M. Miranda, Mathieu Herman, Rong Cheng, Eden Nahmani, Geoffrey Barrett, Elizabeta Micevska, Gaelle Fontaine, Marie Claude Potier, Elizabeth Head, Frederick A. Schmitt, Ira T. Lott, Ivonne Z. Jiménez-Velázquez, Stylianos E. Antonarakis, Gilbert Di Paolo, Joseph H. Lee, S. Abid Hussaini, Catherine Marquer

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD. Miranda et al. combine human genetics, human brain samples, and behavior and electrophysiology in a transgenic mouse model to show that synaptojanin 1 levels regulate the function of place cells in the aging hippocampus. The results have implications for memory deficits in all types of Alzheimer's disease.

Original languageEnglish
Pages (from-to)2967-2975
Number of pages9
JournalCell Reports
Volume23
Issue number10
DOIs
StatePublished - Jun 5 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Keywords

  • Long-term memory
  • SYNJ1
  • hyperexcitability
  • in vivo electrophysiology
  • neurodegenerative disorders
  • single nucleotide polymorphisms
  • synaptic dysfunction

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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