GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

TLDR

During early development, neurons have high intracellular chloride, making GABA excitatory and generating primitive network activity that promotes synchronous firing and cortical wiring. The review examines how GABA’s excitatory action through chloride‑permeable GABA A receptors governs early network development. GABA depolarizes immature neurons via chloride efflux, triggering sodium spikes, activating voltage‑gated calcium channels, and synergizing with NMDA receptors by displacing magnesium. GABA is the principal excitatory transmitter before glutamate, modulating cell cycle, migration, generating giant depolarizing potentials, influencing plasticity and seizures, and providing an evolutionarily conserved mechanism for synapse formation and network activity.

Abstract

Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter γ-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABA A receptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to “wire together” so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.