TY - JOUR
T1 - Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease
AU - Miranda, Andre M.
AU - Herman, Mathieu
AU - Cheng, Rong
AU - Nahmani, Eden
AU - Barrett, Geoffrey
AU - Micevska, Elizabeta
AU - Fontaine, Gaelle
AU - Potier, Marie Claude
AU - Head, Elizabeth
AU - Schmitt, Frederick A.
AU - Lott, Ira T.
AU - Jiménez-Velázquez, Ivonne Z.
AU - Antonarakis, Stylianos E.
AU - Di Paolo, Gilbert
AU - Lee, Joseph H.
AU - Hussaini, S. Abid
AU - Marquer, Catherine
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/6/5
Y1 - 2018/6/5
N2 - 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.
AB - 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.
KW - Long-term memory
KW - SYNJ1
KW - hyperexcitability
KW - in vivo electrophysiology
KW - neurodegenerative disorders
KW - single nucleotide polymorphisms
KW - synaptic dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85047896688&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047896688&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.05.011
DO - 10.1016/j.celrep.2018.05.011
M3 - Article
C2 - 29874583
AN - SCOPUS:85047896688
SN - 2211-1247
VL - 23
SP - 2967
EP - 2975
JO - Cell Reports
JF - Cell Reports
IS - 10
ER -
