|
Mary C. McKenna, Ph.D.
Principal Investigator
University of Maryland School of Medicine
FRAXA Awards:
$53,000 in 2008
$42,000 in
2007
by Mary McKenna, 4/2007
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.
|
