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The Journal of Neuroscience, December 15, 1998, 18(24):10749-10761
Glutamate Inhibits GABA Excitatory Activity in Developing
Neurons
Anthony N.
van den Pol1, 2,
Xiao-Bing
Gao1,
Peter R.
Patrylo1,
Prabhat K.
Ghosh1, and
Karl
Obrietan2
1 Department of Neurosurgery, Yale University, New
Haven, Connecticut 06520, and 2 Department of Biological
Sciences, Stanford University, Stanford, California 94305
In contrast to the mature brain, in which GABA is the major
inhibitory neurotransmitter, in the developing brain GABA can be
excitatory, leading to depolarization, increased cytoplasmic calcium,
and action potentials. We find in developing hypothalamic neurons that
glutamate can inhibit the excitatory actions of GABA, as revealed with
fura-2 digital imaging and whole-cell recording in cultures and brain
slices. Several mechanisms for the inhibitory role of glutamate
were identified. Glutamate reduced the amplitude of the cytoplasmic
calcium rise evoked by GABA, in part by activation of group II
metabotropic glutamate receptors (mGluRs). Presynaptically, activation
of the group III mGluRs caused a striking inhibition of GABA release in
early stages of synapse formation. Similar inhibitory actions of the
group III mGluR agonist L-AP4 on depolarizing GABA activity
were found in developing hypothalamic, cortical, and spinal cord
neurons in vitro, suggesting this may be a widespread mechanism of inhibition in neurons throughout the developing brain. Antagonists of group III mGluRs increased GABA activity, suggesting an
ongoing spontaneous glutamate-mediated inhibition of excitatory GABA
actions in developing neurons. Northern blots revealed that many mGluRs
were expressed early in brain development, including times of
synaptogenesis. Together these data suggest that in developing neurons
glutamate can inhibit the excitatory actions of GABA at both
presynaptic and postsynaptic sites, and this may be one set of
mechanisms whereby the actions of two excitatory transmitters, GABA and
glutamate, do not lead to runaway excitation in the developing brain.
In addition to its independent excitatory role that has been the
subject of much attention, our data suggest that glutamate may also
play an inhibitory role in modulating the calcium-elevating actions of
GABA that may affect neuronal migration, synapse formation, neurite
outgrowth, and growth cone guidance during early brain development.
Key words:
hypothalamus; metabotropic glutamate receptor; calcium; developing synapse; spinal cord; cortex
Copyright © 1998 Society for Neuroscience 0270-6474/98/182410749-13$05.00/0
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