|Role of fragile X mental retardation protein in metabotropic glutamate receptor-dependent synaptic plasticity-Fellowship 2001-2
by Kimberly Huber, 10/1/2002
This grant was funded by FRAXA with help from The Meadows Foundation.
Our research focuses on how connections between brain
cells, called synapses, change in a long term way, termed synaptic plasticity. It is thought
that long-term changes at synapses underlie the refinement of neuronal circuitry during development and mediate processes such as learning and memory in the adult. In the past few years we have been studying synaptic plasticity, in a mouse model of mental retardation, specifically fragile X syndrome. The 'fragile X' mouse model was generated by a knockout or removal of the Fragile X mental retardation gene (Fmr1) gene.
To try and understand how synaptic function and plasticity is changed in fragile X syndrome, we studied a form of synaptic weakening, termed long-term depression or LTD, in the fragile X mouse. We have found that LTD is larger in fragile X mice when compared to their normal littermates. This result suggests a potential function for fragile X protein and how abnormal synapse maturation occurs as a consequence of its loss. This result was published this year in Proceedings of the National Academy of Sciences (Huber et al., 2002).
The fact that LTD is larger in fragile X syndrome may provide an avenue which to test therapeutic strategies for treatment of fragile X syndrome. We have done considerable work determining the cellular mechanisms which underlie LTD in rats and know that it requires activation of a subclass of neurotransmitter receptors called metabotropic glutamate receptors or mGluRs. We are currently testing mGluR antagonists with different subtype specificities to find a compound which can reduce LTD in fragile X mice to levels observed in normal mice. We have had success reducing LTD in rats with one mGluR1 antagonist, termed LY367385. We plan to continue testing mGluR1 antagonists in fragile X mice and test them in combination with other mGluR antagonists. In addition, we have demonstrated that LTD occurs in developing synapses in rats and plan to test if LTD is altered in young fragile X mice. This may help to understand why synapses of fragile X syndrome patients and mice have immature synapses.
In the third aim, we have planned experiments which will reveal the cellular mechanisms by which the fragile X protein enhances LTD. This proposed research is expected to lead to therapeutic strategies for the treatment of fragile X syndrome with mGluR antagonists. Furthermore, information about the age-dependent function of fragile X protein could predict the best developmental window for these treatments. We also aim to determine why synaptic plasticity is altered in fragile X syndrome which may lead to hypotheses about the mechanisms of abnormal synapse maturation and cognitive deficits associated with the disease.
Our initial findings that LTD is enhanced in fragile X mice was instrumental in obtaining a McKnight Neuroscience of Brain Disorders award from the McKnight Endowment Fund for Neuroscience. This additional funding has allowed us to expand our efforts to determine the synaptic mechanisms of LTD in cultured neurons, determine how mGluRs contribute to synapse development and develop genetic rescue strategies by transfection of neurons with Fmr1 gene.
The enhancement of LTD in a mental retardation model suggests that pharmacological methods to reduce LTD to normal levels are a potential strategy to treat fragile X syndrome. Results of the proposed research are expected to provide the framework for future clinical trials and facilitate progress towards a treatment of fragile X syndrome.