Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus

Steven A. Connor, Charles A. Hoeffer, Eric Klann, Peter V. Nguyen

Research output: Contribution to journalArticle

Abstract

Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the β-adrenergic receptor (β-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that β-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.

Original languageEnglish (US)
Pages (from-to)207-220
Number of pages14
JournalLearning and Memory
Volume18
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Fragile X Mental Retardation Protein
Long-Term Potentiation
Hippocampus
Knockout Mice
Emetine
Fragile X Syndrome
Depression
Adrenergic Agonists
Metabotropic Glutamate Receptors
Isoproterenol
Intellectual Disability
Genes
Proteins
Genotype

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience
  • Neuropsychology and Physiological Psychology

Cite this

Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus. / Connor, Steven A.; Hoeffer, Charles A.; Klann, Eric; Nguyen, Peter V.

In: Learning and Memory, Vol. 18, No. 4, 04.2011, p. 207-220.

Research output: Contribution to journalArticle

Connor, Steven A. ; Hoeffer, Charles A. ; Klann, Eric ; Nguyen, Peter V. / Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus. In: Learning and Memory. 2011 ; Vol. 18, No. 4. pp. 207-220.
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