Fragile X syndrome (FXS) is the most common genetically inherited form of mental retardation affecting approximately 1 in 3-4000 boys in the UK. FXS results from the silencing of the fragile X mental retardation 1 gene (FMR1) and loss of the protein it encodes (fragile X mental retardation protein, FMRP). FMRP is believed to play an important role in the development and regulation of excitatory synaptic transmission (Pfeiffer & Huber, 2009) and in particular, loss of FMRP has been reported to impair synaptic plasticity (Huber et al. 2002) and basal synaptic transmission in the hippocampus of Fmr1-null mutant mice. At Schaffer collateral/commissural inputs to hippocampal CA1 pyramidal neurones, we have examined metabotropic glutamate receptor (mGluR)-induced long-term depression (LTD) using the group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG; 30 or 100 µM). In vitro, extracellular field recordings from hippocampal slices revealed that mGluR-LTD is enhanced in male Fmr1-/y mice relative to wild type (WT) littermates (30 µM 80.5 ± 9 %, Fmr1-/y, n = 7 versus 99.1 ± 9 %, WT, n = 9; 100 µM 63 ± 4%, Fmr1-/y, n = 19 versus 77 ± 5%, WT, n = 17). In Fmr1-/y mice this form of synaptic plasticity was independent of new protein synthesis since in the presence of anisomycin (20 µM) LTD was still induced and maintained at similar levels (65 ± 7%, n = 9) as were observed in recordings in the absence of anisomycin. In slices from WT mice anisomycin prevented the maintainence of LTD (91 ± 5%, n = 8). In addition, we examined mGluR-induced alterations in intrinsic membrane properties – a recently characterized form of plasticity that has not previously been examined in Fmr1-/y mice (Brager & Johnston, 2007). No detectable impairments were evident among our data, which measured the relative change in input resistance, resting potential, sag ratio and rheobase before and after DHPG application (WT, n = 19; Fmr1-/y, n = 17). These findings suggest that disruptions in mGluR-LTD in Fmr1-/y mice are due to changes at the synapse rather than alterations in the intrinsic properties of CA1 pyramidal neurones. Currently, we are investigating mGluR-dependent signaling cascades that may be implicated in synaptic plasticity deficits observed in our mouse model of FXS.