GABA and glycine in the developing brain

Abstract

GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels. During early developmental periods, both GABA and glycine depolarize membrane potentials due to the relatively high intracellular Cl(-) concentration. Therefore, they can act as excitatory neurotransmitters. GABA and glycine are involved in spontaneous neural network activities in the immature CNS such as giant depolarizing potentials (GDPs) in neonatal hippocampal neurons, which are generated by the synchronous activity of GABAergic interneurons and glutamatergic principal neurons. GDPs and GDP-like activities in the developing brains are thought to be important for the activity-dependent functiogenesis through Ca(2+) influx and/or other intracellular signaling pathways activated by depolarization or stimulation of metabotropic receptors. However, if GABA and glycine do not shift from excitatory to inhibitory neurotransmitters at the birth and in maturation, it may result in neural disorders including autism spectrum disorders.

Keywords: Activity dependent functiogenesis; GABA; Giant depolarizing potentials; Glycine.

Fig. 1

Schematic representation of a recording of GDPs in an immature rat hippocampal CA3 neuron. a GDPs are seen as large depolarizing events among GABAergic spontaneous synaptic potentials. GDPs are GABA-mediated spontaneous pulsatile depolarizing events that occur at a frequency of 0.005–0.2 Hz. b A typical GDP rises abruptly concomitant with several action potentials, decays within 200–300 ms, and is followed by transient hyperpolarization. c Electrical stimulation at the hilus evokes a depolarizing event similar to a GDP after a stimulus intensity dependent short latency

Fig. 2

Ca²⁺ influx by GABAergic neural inputs in an immature neuron in immature neurons, NKCC1 is more active than KCC2 and intracellular Cl⁻ concentration is maintained at a relatively high level. GABA released from GABAergic interneurons opens GABA_A receptor Cl⁻ channels and Cl⁻ efflux results in the depolarization of the neuron. Depolarization opens voltage dependent calcium channels (VDCC) and removes bound Mg²⁺ from NMDA receptors, resulting in Ca²⁺ influx through VDCCs and glutamate-activated NMDA receptors. (The glycine binding site on NMDA receptors has been omitted)

Fig. 3

Schematic membrane potential responses of rat neonatal CA3 neurones to GABA and glycine bath application of GABA and glycine lead to quite identical responses on neonatal CA3 neurone in the presence of TTX, except that GABA and glycine were specifically antagonized by bicuculline and strychnine, respectively, and glycine response disappeared in the 3rd neonatal week. Responses changed polarity from depolarization to hyperpolarization between the 1st and the 2nd postnatal weeks, despite the resting membrane potential remaining unchanged at approximately −65 mV

Fig. 4

The time course of the change in neural intracellular Cl⁻ concentration during early developmental periods. a During the embryonic and early neonatal periods, NKCC1 is more active than KCC2 and the reversal potential for Cl⁻ is maintained above the resting potential. However, at the birth, maternal oxytocin acts on the fetal neurons and suppresses NKCC1 activity resulting in a transient hyperpolarizing shift of Cl⁻ reversal potential. After birth, KCC2 becomes gradually more active than NKCC1 and the Cl⁻ reversal potential finally becomes more negative than the resting potential. Failure of sufficient oxytocin action at birth has been suggested to be a cause of pathological conditions such as autism spectrum disorders. b Responses to GABA and glycine change from excitatory to inhibitory between the 1st and the 2nd postnatal weeks due to the increase of intracellular Cl⁻ concentration