Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome

Henry G S Martin; Olivier Lassalle; Jonathan T Brown; Olivier J Manzoni

doi:10.1093/cercor/bhv031

Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome

Cereb Cortex. 2016 May;26(5):2084-2092. doi: 10.1093/cercor/bhv031. Epub 2015 Mar 5.

Authors

Henry G S Martin^{1

2

3}, Olivier Lassalle^{1

2

3}, Jonathan T Brown⁴, Olivier J Manzoni^{1

2

3}

Affiliations

¹ INSERM U901, Marseille 13009, France.
² INMED, Marseille 13009, France.
³ Université de Aix-Marseille, UMR S901, Marseille, France.
⁴ Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.

PMID: 25750254
DOI: 10.1093/cercor/bhv031

Abstract

The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1KO mice from 2 to 12 months. In young adult Fmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1KO mice, which may correlate to some of the complex age-related deficits in FXS.

Keywords: Fragile X; LTP; NMDA receptor; mGlu receptor; synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Animals
Disease Models, Animal
Electric Stimulation
Excitatory Postsynaptic Potentials / drug effects
Fragile X Mental Retardation Protein / genetics
Fragile X Mental Retardation Protein / physiology*
Fragile X Syndrome / genetics
Fragile X Syndrome / physiopathology*
Long-Term Potentiation*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / drug effects
Neurons / physiology*
Prefrontal Cortex / drug effects
Prefrontal Cortex / physiopathology*
Pyridines / pharmacology
Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
Receptor, Metabotropic Glutamate 5 / physiology
Receptors, AMPA / physiology
Receptors, N-Methyl-D-Aspartate / physiology

Substances

Fmr1 protein, mouse
Grm5 protein, mouse
Pyridines
Receptor, Metabotropic Glutamate 5
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
Fragile X Mental Retardation Protein
6-methyl-2-(phenylethynyl)pyridine