by Mary McKenna, 4/1/2007
Over activation of metabotropic glutamate receptors (mGluR) is thought to be involved in the symptoms of fragile X syndrome. Although mGluR activation involves glutamatergic neurotransmission, there is little or no information about how the increased mGluR activation affects glutamate metabolism in brain. Since ongoing neurotransmission requires coordinated interactions between synapses and surrounding astrocytes that remove glutamate from the extracellular space, and mGluRs are localized on both postsynaptic dendrites and astrocytes, increased activation of mGluR could alter both neuronal and astrocyte specific aspects of glutamate metabolism.
Our studies focus on identifying the effects of the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on cell specific differences in the amount and pathways of glutamate, GABA and glutamine metabolism in brains of a mouse knockout model (KO) for fragile X syndrome (JAX B6.129 P2-Fmr1tm1Cgr) (Fmr1 KO) and controls. Preliminary data from our lab suggests that synthesis of glutamate, GABA and glutamine is increased in the brain of Fmr1 KO mice compared to controls and that the synthesis is normalized in brain of Fmr1 KO mice treated with MPEP. We will determine the neuronal and astrocytic specific effects of MPEP on the alterations in glutamate, GABA and glutamine metabolism and neuronal-glial interactions in brains of Fmr1 KO mice and controls using the powerful, state of the art technique of ex vivo 13C-nuclear magnetic resonance (NMR) spectroscopy. Since our preliminary data show evidence of alterations in both neuronal and astrocyte metabolism we will use specific precursor molecules that allow us to determine metabolism primarily in neurons and neuronal - glial trafficking of molecules ([1,6-13C]glucose), and in astrocytes and glial - neuronal trafficking of molecules ([1,2-13C]acetate).
This approach will provide important new information since little is known about cell specific alterations in metabolism in fragile X syndrome or the effects of MPEP on neuronal and astrocytic metabolism. These studies will yield a wealth of new data about the alterations in neurotransmitter synthesis and metabolism in Fmr1 KO mouse brain, and provide a greater understanding of the alterations in metabolism that may occur in patients with fragile X syndrome. In addition any alterations found in enzymes or transport proteins in Fmr1 mouse brain may be potential targets for new therapeutic interventions.