GABA-mediated membrane oscillations as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus

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Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus and spinal cord. In the immature hippocampus the so-called ‘giant depolarizing potentials’ (GDPs) are network-driven membrane oscillations characterized by recurrent membrane depolarization with superimposed fast action potentials. Usually, they last hundreds of ms and are separated by intervals of several seconds. GDPs depend on the synergistic action of GABA and glutamate acting on GABAA and (RS)-a-amino-3-hydroxy-5-methyl-4-isoxadepropionate (AMPA) receptors, respectively. Early in postnatal life, GABA depolarizes and excites the postsynaptic cells due to high intracellular [Cl-] which results mainly from the unbalance of two Cl- co-transporter systems, the NKCCl and KCC2 that enhance and lower intracellular [Cl-], respectively. In accord with the Hebb postulate on activity-dependent synaptic strengthening, here the hypothesis has been tested that GDPs may act as coincident detector signals between pre and postsynaptic activity. This assumption has been verified at poorly developed mossy fiber (MF)-CA3 connections. These synapses are particularly interesting because they can release GABA in addition to glutamate. We found that during the first postnatal week correlated pre (MF) and postsynaptic (GDPs) activity persistently enhances synaptic strength at MF-CA3 connections. This effect was usually restricted to the activated synapse. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and disappeared. The potentiation depended on the activation of voltage-dependent calcium channels and calcium flux. Moreover, it was clear from our experiments that at this developmental stage GABA is the main neurotransmitter released from the MF. This is consistent with the sequential expression of functional GABA and glutamatergic synapses found in the hippocampus at early developmental stages. Synchronous membrane oscillations may therefore contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit. Later in development when the degree of functional connections is sufficiently high, GDPs would be replaced by more subtle types of signal synchronization such as theta or gamma activity characteristic of the adult network.