Puritan's View of the “Ménage à Trois”

Commentary The Puritan tradition of New England radiates well beyond the established New England area. So, let’s have a cleansing look at one of the concepts, which emanated over 25 years ago and was promoted in the famous Ben-Ari’s review of 1997 (1). This is the concept of critical interplay among three major neurotransmitter players in the developing brain: AMPA, NMDA, and GABAA transmission. According to the original scenario, GABAA receptors are swinging from mediating early life depolarizing actions to later in life hyperpolarizing effects. In the beginning, there was a study of Ben-Ari (2) showing age-dependent appearance of giant depolarizing potentials in the hippocampal CA3 region that could be blocked by bicuculline (a GABAA receptor antagonist), which were commonly present up to postnatal day P8 and completely disappeared by P12. Staley and Mody (3) later demonstrated depolarizing actions of GABA in adult hippocampal dentate gyrus granule cells leading, in that case, to shunting the membrane for subsequent glutamatergic transmission. The reason was reversal potential for chloride ions of −66 mV (their flux is mediated by GABAA receptors) that was significantly more positive than resting membrane potential of granule cells recorded at −85 mV. After opening of the GABAA receptor channel, chloride ions leaked from the cell into the extracellular space (opposite from the usual) carrying a negative charge, thus causing a depolarizing current (the intracellular space becomes more positively charged). This study provided conceptual proof that, depending on the intracellular chloride concentration and resting membrane potential, opening GABAA receptor channels may lead either to hyperpolarization (the GABAA receptor as we used to know) or to depolarization. Since depolarization is frequently and subconsciously associated with excitation, the term “excitatory effects of GABA” was coined (4). The intracellular concentration of chloride ions was the most significant contributing factor to this dual (depolarizing vs hyperpolarizing) role of GABA mediated via GABAA receptors. Indeed, during the neonatal and early postnatal periods, major changes happen to the neuronal proteins serving as chloride transporters/cotransporters responsible for intracellular chloride concentration. The transporter that pumps chloride into the cell, the sodium-potassium-chloride (×2) cotransporter (NKCC1), has a substantial presence at birth, and its expression slightly decreases with development (5). However, the chloride extruding protein (potassiumchloride cotransporter; KCC2) is present in the rat brain only minimally after birth and its concentration rises fourfold by P28 (6). These findings provide a framework for the switch from depolarizing actions mediated by GABAA receptors in the neonatal rodent brain to hyperpolarizing actions anytime between P7–P14. This was exciting news: The concept could rationalize not only the increased excitability of the immature brain (7)—a settled paradigm that was very difficult to explain mechanistiAn Optogenetic Approach for Investigation of Excitatory and Inhibitory Network GABA Actions in Mice Expressing Channelrhodopsin-2 in GABAergic Neurons.