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The Journal of Neuroscience, October 12, 2005, 25(41):9460-9469; doi:10.1523/JNEUROSCI.2638-05.2005

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Neurobiology of Disease
Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein

John Larson, Ruth E. Jessen, Daniel Kim, Ananda-Kriiya S. Fine, and Johann du Hoffmann

Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, Illinois 60612

Synaptic function and plasticity were studied in mice lacking the fragile X mental retardation protein (FMRP), a model for the fragile X mental retardation syndrome. Associational connections were studied in slices of anterior piriform (olfactory) cortex, and Schaffer-commissural synapses were studied in slices of hippocampus. Knock-out (KO) mice lacking FMRP were compared with congenic C57BL/6J wild-type (WT) controls. Input-output curves and paired-pulse plasticity were not significantly altered in KO compared with WT mice in either the olfactory cortex or hippocampus. Long-term potentiation (LTP) induced by theta burst stimulation in the anterior piriform cortex was normal in KO mice aged <6 months but was impaired in KO mice aged > 6 months. The deficit in LTP was significant in mice aged 6-12 months and more pronounced in mice aged 12-18 months. Similar differences between WT and KO mice were seen whether LTP was induced in the presence or absence of a GABA_A receptor blocker. Postsynaptic responses to patterned burst stimulation in KO mice showing impaired LTP were not significantly different from those in WT mice, suggesting that the LTP deficit was not caused by alterations in circuit properties. No differences in hippocampal LTP were observed in WT and KO mice at any ages. The results indicate that FMRP deficiency is associated with an age-dependent and region-selective impairment in long-term synaptic plasticity.

Key words: fragile X syndrome; FMRP; LTP; synaptic plasticity; olfactory cortex; hippocampus

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Received June 27, 2005; revised August 10, 2005; accepted September 3, 2005.

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