Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration

Laura N. Smith; Jakub P. Jedynak; Miles R. Fontenot; Carly F. Hale; Karen C. Dietz; Makoto Taniguchi; Feba S. Thomas; Benjamin C. Zirlin; Shari G. Birnbaum; Kimberly M. Huber; Mark J Thomas; Christopher W. Cowan

doi:10.1016/j.neuron.2014.03.028

Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration

Laura N. Smith, Jakub P. Jedynak, Miles R. Fontenot, Carly F. Hale, Karen C. Dietz, Makoto Taniguchi, Feba S. Thomas, Benjamin C. Zirlin, Shari G. Birnbaum, Kimberly M. Huber, Mark J Thomas, Christopher W. Cowan

Neuroscience

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

54 Scopus citations

Abstract

Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend tonatural reward. We find that FMRP functions inthe adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.

Original language	English (US)
Pages (from-to)	645-658
Number of pages	14
Journal	Neuron
Volume	82
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2014.03.028
State	Published - May 7 2014

Bibliographical note

Funding Information:
The authors thank Marissa Baumgardner, Lindsey Williams, Dr. Julia Wilkerson, Sarah Jenevein, Dr. Seth Hays, and Katie Schaukowitch for technical assistance; Ami Pettersen and Lauren Peca for behavioral assistance; and Dr. David Nelson for generously sharing the floxed Fmr1 conditional KO mouse line. We thank Dr. Rachel Penrod for insightful comments on the written manuscript. L.N.S. was supported by fellowships from the National Institute on Drug Abuse (NIDA) (T32 DA007290 and F32 DA027265) and the FRAXA Research Foundation. We also acknowledge the generous support of the Simons Foundation (Simons Foundation Autism Research Initiative grant to C.W.C. and K.M.H.), NIDA (DA008277, DA027664, and DA030590 to C.W.C. and DA019666, R21DA033457, and K02DA035459 to M.J.T.), and the National Institute of Neurological Disorders and Stroke (NS062158 to M.J.T.).

UN SDGs

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

Publisher link

10.1016/j.neuron.2014.03.028

Find It

Find It at U of M Libraries

Cite this

Smith, L. N., Jedynak, J. P., Fontenot, M. R., Hale, C. F., Dietz, K. C., Taniguchi, M., Thomas, F. S., Zirlin, B. C., Birnbaum, S. G., Huber, K. M., Thomas, M. J., & Cowan, C. W. (2014). Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration. Neuron, 82(3), 645-658. https://doi.org/10.1016/j.neuron.2014.03.028

@article{a871aa8e363a457490edc497c1aa36cf,

title = "Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration",

abstract = "Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend tonatural reward. We find that FMRP functions inthe adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.",

author = "Smith, {Laura N.} and Jedynak, {Jakub P.} and Fontenot, {Miles R.} and Hale, {Carly F.} and Dietz, {Karen C.} and Makoto Taniguchi and Thomas, {Feba S.} and Zirlin, {Benjamin C.} and Birnbaum, {Shari G.} and Huber, {Kimberly M.} and Thomas, {Mark J} and Cowan, {Christopher W.}",

note = "Funding Information: The authors thank Marissa Baumgardner, Lindsey Williams, Dr. Julia Wilkerson, Sarah Jenevein, Dr. Seth Hays, and Katie Schaukowitch for technical assistance; Ami Pettersen and Lauren Peca for behavioral assistance; and Dr. David Nelson for generously sharing the floxed Fmr1 conditional KO mouse line. We thank Dr. Rachel Penrod for insightful comments on the written manuscript. L.N.S. was supported by fellowships from the National Institute on Drug Abuse (NIDA) (T32 DA007290 and F32 DA027265) and the FRAXA Research Foundation. We also acknowledge the generous support of the Simons Foundation (Simons Foundation Autism Research Initiative grant to C.W.C. and K.M.H.), NIDA (DA008277, DA027664, and DA030590 to C.W.C. and DA019666, R21DA033457, and K02DA035459 to M.J.T.), and the National Institute of Neurological Disorders and Stroke (NS062158 to M.J.T.). ",

year = "2014",

month = may,

day = "7",

doi = "10.1016/j.neuron.2014.03.028",

language = "English (US)",

volume = "82",

pages = "645--658",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration

AU - Smith, Laura N.

AU - Jedynak, Jakub P.

AU - Fontenot, Miles R.

AU - Hale, Carly F.

AU - Dietz, Karen C.

AU - Taniguchi, Makoto

AU - Thomas, Feba S.

AU - Zirlin, Benjamin C.

AU - Birnbaum, Shari G.

AU - Huber, Kimberly M.

AU - Thomas, Mark J

AU - Cowan, Christopher W.

N1 - Funding Information: The authors thank Marissa Baumgardner, Lindsey Williams, Dr. Julia Wilkerson, Sarah Jenevein, Dr. Seth Hays, and Katie Schaukowitch for technical assistance; Ami Pettersen and Lauren Peca for behavioral assistance; and Dr. David Nelson for generously sharing the floxed Fmr1 conditional KO mouse line. We thank Dr. Rachel Penrod for insightful comments on the written manuscript. L.N.S. was supported by fellowships from the National Institute on Drug Abuse (NIDA) (T32 DA007290 and F32 DA027265) and the FRAXA Research Foundation. We also acknowledge the generous support of the Simons Foundation (Simons Foundation Autism Research Initiative grant to C.W.C. and K.M.H.), NIDA (DA008277, DA027664, and DA030590 to C.W.C. and DA019666, R21DA033457, and K02DA035459 to M.J.T.), and the National Institute of Neurological Disorders and Stroke (NS062158 to M.J.T.).

PY - 2014/5/7

Y1 - 2014/5/7

N2 - Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend tonatural reward. We find that FMRP functions inthe adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.

AB - Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend tonatural reward. We find that FMRP functions inthe adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.

UR - http://www.scopus.com/inward/record.url?scp=84899846212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899846212&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2014.03.028

DO - 10.1016/j.neuron.2014.03.028

M3 - Article

C2 - 24811383

AN - SCOPUS:84899846212

SN - 0896-6273

VL - 82

SP - 645

EP - 658

JO - Neuron

JF - Neuron

IS - 3

ER -

Fragile X Mental Retardation Protein Regulates Synaptic and Behavioral Plasticity to Repeated Cocaine Administration

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this