MGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

Rocco G. Gogliotti; Rebecca K. Senter; Nicole M. Fisher; Jeffrey Adams; Rocio Zamorano; Adam G. Walker; Anna L. Blobaum; Darren W. Engers; Corey R. Hopkins; J. Scott Daniels; Carrie K. Jones; Craig W. Lindsley; Zixiu Xiang; P. Jeffrey Conn; Colleen M. Niswender

doi:10.1126/scitranslmed.aai7459

MGlu₇ potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

Rocco G. Gogliotti, Rebecca K. Senter, Nicole M. Fisher, Jeffrey Adams, Rocio Zamorano, Adam G. Walker, Anna L. Blobaum, Darren W. Engers, Corey R. Hopkins, J. Scott Daniels, Carrie K. Jones, Craig W. Lindsley, Zixiu Xiang, P. Jeffrey Conn, Colleen M. Niswender

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu₇) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu₇ protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu₇-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu₇ activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu₇ positive allosteric modulation decreases apneas in Mecp2^+/- mice, suggesting that mGlu₇ may be a potential therapeutic target for multiple aspects of the RTT phenotype.

Original language	English (US)
Article number	eaai7459
Journal	Science translational medicine
Volume	9
Issue number	403
DOIs	https://doi.org/10.1126/scitranslmed.aai7459
State	Published - Aug 16 2017
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Gogliotti, R. G., Senter, R. K., Fisher, N. M., Adams, J., Zamorano, R., Walker, A. G., Blobaum, A. L., Engers, D. W., Hopkins, C. R., Daniels, J. S., Jones, C. K., Lindsley, C. W., Xiang, Z., Conn, P. J., & Niswender, C. M. (2017). MGlu₇ potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science translational medicine, 9(403), Article eaai7459. https://doi.org/10.1126/scitranslmed.aai7459

Gogliotti, RG, Senter, RK, Fisher, NM, Adams, J, Zamorano, R, Walker, AG, Blobaum, AL, Engers, DW, Hopkins, CR, Daniels, JS, Jones, CK, Lindsley, CW, Xiang, Z, Conn, PJ & Niswender, CM 2017, 'MGlu₇ potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome', Science translational medicine, vol. 9, no. 403, eaai7459. https://doi.org/10.1126/scitranslmed.aai7459

@article{9b2d0c365f5b488bab109f42084c2325,

title = "MGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome",

abstract = "Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7 positive allosteric modulation decreases apneas in Mecp2+/- mice, suggesting that mGlu7 may be a potential therapeutic target for multiple aspects of the RTT phenotype.",

author = "Gogliotti, {Rocco G.} and Senter, {Rebecca K.} and Fisher, {Nicole M.} and Jeffrey Adams and Rocio Zamorano and Walker, {Adam G.} and Blobaum, {Anna L.} and Engers, {Darren W.} and Hopkins, {Corey R.} and Daniels, {J. Scott} and Jones, {Carrie K.} and Lindsley, {Craig W.} and Zixiu Xiang and Conn, {P. Jeffrey} and Niswender, {Colleen M.}",

note = "Funding Information: For mouse total protein preparation, the cortex, hippocampus, and striatum were microdissected from P39 to P55 Mecp2−/y, 20-week Mecp2+/−, and control mice. For human motor cortex protein preparation, frozen sections were obtained from the University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of the National Institutes of Health NeuroBioBank, and the Harvard Brain Tissue Resource Center, which is supported in part by Public Health Service contract HHSN-271-2013-00030C. Total protein was prepared as described in (12), and synaptosome preparations were prepared as described in (53).",

year = "2017",

month = aug,

day = "16",

doi = "10.1126/scitranslmed.aai7459",

language = "English (US)",

volume = "9",

journal = "Science translational medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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T1 - MGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

AU - Gogliotti, Rocco G.

AU - Senter, Rebecca K.

AU - Fisher, Nicole M.

AU - Adams, Jeffrey

AU - Zamorano, Rocio

AU - Walker, Adam G.

AU - Blobaum, Anna L.

AU - Engers, Darren W.

AU - Hopkins, Corey R.

AU - Daniels, J. Scott

AU - Jones, Carrie K.

AU - Lindsley, Craig W.

AU - Xiang, Zixiu

AU - Conn, P. Jeffrey

AU - Niswender, Colleen M.

N1 - Funding Information: For mouse total protein preparation, the cortex, hippocampus, and striatum were microdissected from P39 to P55 Mecp2−/y, 20-week Mecp2+/−, and control mice. For human motor cortex protein preparation, frozen sections were obtained from the University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of the National Institutes of Health NeuroBioBank, and the Harvard Brain Tissue Resource Center, which is supported in part by Public Health Service contract HHSN-271-2013-00030C. Total protein was prepared as described in (12), and synaptosome preparations were prepared as described in (53).

PY - 2017/8/16

Y1 - 2017/8/16

N2 - Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7 positive allosteric modulation decreases apneas in Mecp2+/- mice, suggesting that mGlu7 may be a potential therapeutic target for multiple aspects of the RTT phenotype.

AB - Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7 positive allosteric modulation decreases apneas in Mecp2+/- mice, suggesting that mGlu7 may be a potential therapeutic target for multiple aspects of the RTT phenotype.

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AN - SCOPUS:85027731006

SN - 1946-6234

VL - 9

JO - Science translational medicine

JF - Science translational medicine

IS - 403

M1 - eaai7459

ER -

MGlu₇ potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

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