Functional rescue of excitatory synaptic transmission in the developing hippocampus in Fmr1-KO mouse

Pharmaceutical treatments are being developed to correct specific behavioural and morphological aspects of neurodevelopmental disorders such as mental retardation. Fragile X syndrome is an X-linked mental retardation with abnormal dendritic protrusions from neurons in the brain. Increased signalling via excitatory metabotropic glutamate receptor (mGluR) pathways is hypothesised to contribute to this disorder. Targeting these receptors has shown improvements in both behaviour and morphology with the Fmr1-KO mouse model for the syndrome. It is not known whether similar changes occur in excitatory synaptic activity following treatment with mGluR antagonists.We tested the effects of prolonged mGluR blockade on excitatory synaptic activity at three developmental time points in hippocampal slices. We observed a rescue effect of the antagonist MPEP upon spontaneous EPSC amplitude and charge at 2 weeks but not 1 week or 8–10 weeks of development. These data support the role of mGluR antagonist treatment for functional synaptic correction at an early developmental stage in a model for fragile X syndrome.

Research Highlights
► Excitatory synaptic drive is lower in 2-week-old Fmr1-KO hippocampal neurons.
► No differences in excitatory drive are seen at two other developmental time points.
► The mGluR antagonist, MPEP, rescued excitatory synaptic function in Fmr1-KO neurons.