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

doi:10.1016/j.celrep.2018.05.011

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

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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 language	English
Pages (from-to)	2967-2975
Number of pages	9
Journal	Cell Reports
Volume	23
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2018.05.011
State	Published - Jun 5 2018

Bibliographical note

Funding Information:
We would like to thank Agnieszka Staniszewski and Dr. Ottavio Arancio for their expert help with behavior studies. We would like to thank Eric Doran and Dr. Sarah B. Martin for their help with DS studies. We want to acknowledge Valerie Savage, Alejandro J. Mercado-Capote, Adithi Jayaraman, and Masayuki Yanagiba for help with microdrive construction and spike sorting. We also want to thank Nicoletta Barolini for her expert help with illustrations and graphics. This work was supported by grants from Fundação para a Ciência e Tecnologia ( PD/BD/105915/2014 to A.M.M.), the Philippe Chatrier Foundation (C.M.), the Lejeune Foundation ( 1149 to G.D.P.), the Alzheimer’s Association ( 2015-NIRG-341570 to S.A.H.), ANR Investissements d’Avenir ( ANR-10-IAIHU-06 to M.-C.P.), and the NIH ( R01AG050425 to S.A.H.; RO1HD064993 to E.H. and F.A.S.; and RO1HD065160, P50AG16573, and U01AG051412 to I.T.L.). Data collection on Caribbean Hispanic families with at least one G206A founder mutation in the PSEN1 gene was supported by the BrightFocus Foundation ( A2015633S ) and NIH /National Institute on Aging ( NIA ) ( R56 AG051876-01A1 ) to J.H.L. Data collection for the EFIGA project was supported by the Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (EFIGA), funded by the NIH/NIA ( 5R37AG015473 , RF1AG015473 , and R56AG051876 ). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study.

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

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.05.011

Cite this

Miranda, A. M., Herman, M., Cheng, R., Nahmani, E., Barrett, G., Micevska, E., Fontaine, G., Potier, M. C., Head, E., Schmitt, F. A., Lott, I. T., Jiménez-Velázquez, I. Z., Antonarakis, S. E., Di Paolo, G., Lee, J. H., Hussaini, S. A., & Marquer, C. (2018). Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Reports, 23(10), 2967-2975. https://doi.org/10.1016/j.celrep.2018.05.011

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

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.",

keywords = "Long-term memory, SYNJ1, hyperexcitability, in vivo electrophysiology, neurodegenerative disorders, single nucleotide polymorphisms, synaptic dysfunction",

author = "Miranda, {Andre M.} and Mathieu Herman and Rong Cheng and Eden Nahmani and Geoffrey Barrett and Elizabeta Micevska and Gaelle Fontaine and Potier, {Marie Claude} and Elizabeth Head and Schmitt, {Frederick A.} and Lott, {Ira T.} and Jim{\'e}nez-Vel{\'a}zquez, {Ivonne Z.} and Antonarakis, {Stylianos E.} and {Di Paolo}, Gilbert and Lee, {Joseph H.} and Hussaini, {S. Abid} and Catherine Marquer",

note = "Funding Information: We would like to thank Agnieszka Staniszewski and Dr. Ottavio Arancio for their expert help with behavior studies. We would like to thank Eric Doran and Dr. Sarah B. Martin for their help with DS studies. We want to acknowledge Valerie Savage, Alejandro J. Mercado-Capote, Adithi Jayaraman, and Masayuki Yanagiba for help with microdrive construction and spike sorting. We also want to thank Nicoletta Barolini for her expert help with illustrations and graphics. This work was supported by grants from Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia ( PD/BD/105915/2014 to A.M.M.), the Philippe Chatrier Foundation (C.M.), the Lejeune Foundation ( 1149 to G.D.P.), the Alzheimer{\textquoteright}s Association ( 2015-NIRG-341570 to S.A.H.), ANR Investissements d{\textquoteright}Avenir ( ANR-10-IAIHU-06 to M.-C.P.), and the NIH ( R01AG050425 to S.A.H.; RO1HD064993 to E.H. and F.A.S.; and RO1HD065160, P50AG16573, and U01AG051412 to I.T.L.). Data collection on Caribbean Hispanic families with at least one G206A founder mutation in the PSEN1 gene was supported by the BrightFocus Foundation ( A2015633S ) and NIH /National Institute on Aging ( NIA ) ( R56 AG051876-01A1 ) to J.H.L. Data collection for the EFIGA project was supported by the Genetic Studies of Alzheimer{\textquoteright}s Disease in Caribbean Hispanics (EFIGA), funded by the NIH/NIA ( 5R37AG015473 , RF1AG015473 , and R56AG051876 ). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. Publisher Copyright: {\textcopyright} 2018 The Authors",

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doi = "10.1016/j.celrep.2018.05.011",

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Miranda, AM, Herman, M, Cheng, R, Nahmani, E, Barrett, G, Micevska, E, Fontaine, G, Potier, MC, Head, E, Schmitt, FA, Lott, IT, Jiménez-Velázquez, IZ, Antonarakis, SE, Di Paolo, G, Lee, JH, Hussaini, SA & Marquer, C 2018, 'Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease', Cell Reports, vol. 23, no. 10, pp. 2967-2975. https://doi.org/10.1016/j.celrep.2018.05.011

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T1 - Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

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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 - Funding Information: We would like to thank Agnieszka Staniszewski and Dr. Ottavio Arancio for their expert help with behavior studies. We would like to thank Eric Doran and Dr. Sarah B. Martin for their help with DS studies. We want to acknowledge Valerie Savage, Alejandro J. Mercado-Capote, Adithi Jayaraman, and Masayuki Yanagiba for help with microdrive construction and spike sorting. We also want to thank Nicoletta Barolini for her expert help with illustrations and graphics. This work was supported by grants from Fundação para a Ciência e Tecnologia ( PD/BD/105915/2014 to A.M.M.), the Philippe Chatrier Foundation (C.M.), the Lejeune Foundation ( 1149 to G.D.P.), the Alzheimer’s Association ( 2015-NIRG-341570 to S.A.H.), ANR Investissements d’Avenir ( ANR-10-IAIHU-06 to M.-C.P.), and the NIH ( R01AG050425 to S.A.H.; RO1HD064993 to E.H. and F.A.S.; and RO1HD065160, P50AG16573, and U01AG051412 to I.T.L.). Data collection on Caribbean Hispanic families with at least one G206A founder mutation in the PSEN1 gene was supported by the BrightFocus Foundation ( A2015633S ) and NIH /National Institute on Aging ( NIA ) ( R56 AG051876-01A1 ) to J.H.L. Data collection for the EFIGA project was supported by the Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (EFIGA), funded by the NIH/NIA ( 5R37AG015473 , RF1AG015473 , and R56AG051876 ). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. Publisher Copyright: © 2018 The Authors

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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.

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KW - in vivo electrophysiology

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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