NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice.

TitleNMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice.
Publication TypeJournal Article
Year of Publication2012
AuthorsEadie, BD, Cushman J, Kannangara TS, Fanselow MS, Christie BR
JournalHippocampus
Volume22
Issue2
Pagination241-54
Date Published2012 Feb
ISSN1098-1063
KeywordsAnimals, Dentate Gyrus, Discrimination (Psychology), Disease Models, Animal, Excitatory Postsynaptic Potentials, Fragile X Mental Retardation Protein, Fragile X Syndrome, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Organ Culture Techniques, Patch-Clamp Techniques, Receptors, N-Methyl-D-Aspartate, Reverse Transcriptase Polymerase Chain Reaction
Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. This X-linked disorder is caused by the transcriptional repression of a single gene, Fmr1. The loss of Fmr1 transcription prevents the production of Fragile X mental retardation protein (FMRP) which in turn disrupts the expression of a variety of key synaptic proteins that appear to be important for intellectual ability. A clear link between synaptic dysfunction and behavioral impairment has been elusive, despite the fact that several animal models of FXS have been generated. Here we report that Fmr1 knockout mice exhibit impaired bidirectional synaptic plasticity in the dentate gyrus (DG) of the hippocampus. These deficits are associated with a novel decrease in functional NMDARs (N-methyl-D-aspartate receptors). In addition, mice lacking the Fmr1 gene show impaired performance in a context discrimination task that normally requires functional NMDARs in the DG. These data indicate that Fmr1 deletion results in significant NMDAR-dependent electrophysiological and behavioral impairments specific to the DG.

DOI10.1002/hipo.20954
Alternate JournalHippocampus