Glutamate inhibits GABA excitatory activity in developing neurons

In contrast to the mature brain, in which GABA is the major inhibitory neur otransmitter, in the developing brain GABA can be excitatory, leading to de polarization, increased cytoplasmic calcium, and action potentials. We find in developing hypothalamic neurons that glutamate can inhibit the excitato ry actions of GABA, as revealed with fura-2 digital imaging and whole-cell recording in cultures and brain slices. Several mechanisms for the inhibito ry role of glutamate were identified. Glutamate reduced the amplitude of th e cytoplasmic calcium rise evoked by GABA, in part by activation of group I I 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 m GluR agonist L-AP4 on depolarizing GABA activity were found in developing h ypothalamic, cortical, and spinal cord neurons in vitro, suggesting this ma y be a widespread mechanism of inhibition in neurons throughout the develop ing brain. Antagonists of group III mGluRs increased GABA activity, suggest ing an ongoing spontaneous glutamate-mediated inhibition of excitatory GABA actions in developing neurons. Northern blots revealed that many mGluRs we re expressed early in brain development, including times of synaptogenesis. Together these data suggest that in developing neurons glutamate can inhib it the excitatory actions of GABA at both presynaptic and postsynaptic site s, and this may be one set of mechanisms whereby the actions of two excitat ory transmitters, GABA and glutamate, do not lead to runaway excitation in the developing brain. In addition to its independent excitatory role that h as 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 outgro wth, and growth cone guidance during early brain development.