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 GABAAreceptor 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.

SUMMARY1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than -51 mV, action potentials greater than 55 mV and membrane input resistances of 117 + 12 MQ. An unusual characteristic of these cells was the presence of spontaneous giant depolarizing potentials (GDPs) which were observed during the first eight postnatal (P) days in over 85 % of neurones. They were less frequent between P9 and P12 (48 %) and disappeared after P12.2. The GDPs were synchronously generated by a population of neurones; they reversed polarity at -27 mV when recorded with KCl-containing electrodes and at -51 mV with potassium acetate-or potassium methylsulphate-filled electrodes.3. The GDPs were blocked by bath application of bicuculline (10 ,UM) or picrotoxin (100-200 /bM). Exogenously applied y-aminobutyric acid (GABA; 0 2-1 mM) induced at resting membrane potential a bicuculline-sensitive membrane depolarization which reversed polarity at -25 and -51 mV when recorded with KCl-or potassium methylsulphate-filled electrodes respectively.4. The GDPs were reduced in frequency or blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-7-phosphonoheptanoate (AP-7; 50 /IM), D(-)2-amino-5-phosphonovalerate ,#M) and (± )3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10-50 pM) or NMDA channel blockers phencyclidine (2 fM) and ketamine (20 #M).5. Stimulation of the hilus during the first week of life evoked a GDP followed by a hyperpolarization. The GDPs were generated by a population of synchronized neurones and reversed polarity at -27 mV with KCl-filled electrodes and at -52 mV with potassium acetate-or potassium methylsulphate-containing electrodes. slices, interictal discharges. These reversed polarity near 0 mV with KCl-or potassium acetate-containing electrodes and were reduced in amplitude and duration by AP-5 (50 /M). 8. During the second week of life, stimulation of the hilus evoked, as in adult CA3 cells, an excitatory postsynaptic potential (EPSP) followed by a fast and a slow inhibitory postsynaptic potential (IPSP). Exogenously applied GABA induced at resting membrane potential a hyperpolarization which reversed polarity at -66 mV with potassium methylsulphate-containing electrodes.9. It is concluded that, in early postnatal life, hippocampal CA3 neurones display spontaneous and evoked GDPs which are mediated by GABA and presynaptically controlled by NMDA receptors.

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