In the immature brain, GABA (gamma-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation while avoiding the potentially toxic effects of a mismatch between GABA-mediated inhibition and glutamatergic excitation. As key elements of this cascade are activity dependent, the formation of inhibition adds an element of nurture to the construction of cortical networks.

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Excitatory actions of gaba during development: the nature of the nurture.

In the mature brain, GABA (gamma-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal.

Is there more to gaba than synaptic inhibition

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(03)00068-7.pdf

Cation–chloride co-transporters in neuronal communication, development and trauma

Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. In this review, we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Studies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABA(A) receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABA(A) receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.

The GABAergic deficit hypothesis of major depressive disorder

Ionic currents and the network-driven patterns they generate differ in immature and adult neurons: The developing brain is not a "small adult brain." One of the most investigated examples is the developmentally regulated shift of actions of the transmitter GABA that inhibit adult neurons but excite immature ones because of an initially higher intracellular chloride concentration [Cl(-)](i), leading to depolarizing and often excitatory actions of GABA instead of hyperpolarizing and inhibitory actions. The levels of [Cl(-)](i) are also highly labile, being readily altered transiently or persistently by enhanced episodes of activity in relation to synaptic plasticity or a variety of pathological conditions, including seizures and brain insults. Among the plethora of channels, transporters, and other devices involved in controlling [Cl(-)](i), two have emerged as playing a particularly important role: the chloride importer NKCC1 and the chloride exporter KCC2. Here, the authors stress the importance of determining how [Cl(-)](i) is dynamically regulated and how this affects brain operation in health and disease. In a clinical perspective, agents that control [Cl(-)](i) and reinstate inhibitory actions of GABA open novel therapeutic perspectives in many neurological disorders, including infantile epilepsies, autism spectrum disorders, and other developmental disorders.

The GABA Excitatory/Inhibitory Shift in Brain Maturation and Neurological Disorders:

GABA emerges as a trophic signal during rat neocortical development in which it modulates proliferation of neuronal progenitors in the ventricular/subventricular zone (VZ/SVZ) and mediates radial migration of neurons from the VZ/SVZ to the cortical plate/subplate (CP/SP) region. In this study we investigated the role of GABA in the earliest phases of neuronal differentiation in the CP/SP. GABAergic-signaling components emerging during neuronal lineage progression were comprehensively characterized using flow cytometry and immunophenotyping together with physiological indicator dyes. During migration from the VZ/SVZ to the CP/SP, differentiating cortical neurons became predominantly GABAergic, and their dominant GABAA receptor subunit expression pattern changed from α4β1γ1 to α3β3γ2γ3 coincident with an increasing potency of GABA on GABAA receptor-mediated depolarization. GABAA autoreceptor/Cl− channel activity in cultured CP/SP neurons dominated their baseline potential and indirectly their cytosolic Ca2+(Ca2+ c) levels via Ca2+ entry through L-type Ca2+channels. Block of this autocrine circuit at the level of GABA synthesis, GABAA receptor activation, intracellular Cl− ion homeostasis, or L-type Ca2+ channels attenuated neurite outgrowth in most GABAergic CP/SP neurons. In the absence of autocrine GABAergic signaling, neuritogenesis could be preserved by depolarizing cells and elevating Ca2+ c. These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABAA autoreceptors and L-type Ca2+ channels.

https://www.jneurosci.org/content/jneuro/21/7/2343.full.pdf

GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels.

Sabeen Chaudry

Papers

GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels.