Glutamate Inhibits GABA Excitatory Activity in Developing Neurons

Abstract

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.

Levels of Amino Acid Neurotransmitters during Neurogenesis and in Histotypic Cultures of Mouse Spinal Cord

“…On the other hand, as compared with the developmental variations of glutamate and glycine, significant decreases in taurine levels were also observed during three stages: between E15 and E16, between P3 and P7, and in the young adult age, which seems to reinforce the role of taurine in spinal cord neurotransmission. Taurine is known to activate glycine and GABA A receptors during early neocortical development; various reports have demonstrated that these receptors have an excitatory influence in the developing neocortex, leading to increased synaptic activity and elevation of intracellular calcium [11,21,35,69]. As shown in table 1, the ratio of taurine to glutamate in the developing spinal cord varied from 2-to 4-fold, and the ratio of taurine to glycine, from 2-to 6-fold; in the adult stage, both ratios gave values of 1:1.…”

“…The onset of synaptogenesis in spinal motoneurons occurs at E16-E17, when most of the synaptic contacts are formed by glycinergic and GABAergic neurons; excitatory synapses are established on all motoneurons by E19 [33]. The pattern of functional expression suggests that, during the embryonic period until at least 1-2 days after birth, glycine and GABA generate chloride-dependent membrane depolarizations in spinal motoneurons, but it is not known at what age the agonists begin to produce membrane hyperpolarizations [34][35][36].…”

Enhanced Cytomegalovirus Infection of Developing Brain Independent of the Adaptive Immune System

“…A shutter blocked the fluorescent light between data captures. In time-lapse recordings, one image was saved every 4 s. During recording, slices were maintained in a HEPES buffer (44). After we recorded a control baseline fluorescence, the cells were stimulated with a micropipette as described elsewhere (12).…”

Low concentrations of methamidophos do not alter AChE activity but modulate neurotransmitters uptake in hippocampus and striatum in vitro

“…Alterations in glutamate levels may alter several processes that are dependent on normal levels of this neurotransmitter, such as regulation of the nervous system development (McDonald and Johnston, 1990;Komuro and Rakic, 1993;Johnston, 1995;LaMantia, 1995;Vallano, 1998), neuronal migration (Komuro and Rakic, 1993;Rossi and Slater, 1993), outgrowth of neuronal processes (Pearce et al, 1987;Rajan et al, 1999), normal organization of the somatosensory cortex (Fox et al, 1996) as well as GABAergic activity (Van den Pol et al, 1998). In line with the importance of the glutamatergic signaling, both overstimulation (Johnston, 1995) and understimulation of glutamate receptors are harmful to the developing brain (Ikonomidou et al, 2000).…”