At immature mossy fibers-CA3 connections, activation of presynaptic GABAB receptors by endogenously released GABA contributes to synapses silencing

Victoria F Safiulina

doi:10.3389/neuro.03.001.2009

Abstract

Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF) which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABAB autoreceptors by GABA is responsible for the low probability of release and synapse silencing. Blocking GABAB receptors with CGP55845 enhanced the probability of GABA release and switched on silent synapses while the opposite was observed with baclofen. Both these effects were presynaptic and were associated with changes in paired-pulse ratio and coefficient of variation. In addition, enhancing the extracellular GABA concentration by repetitive stimulation of MF or by blocking the GABA transporter GAT-1, switched off active synapses, an effect that was prevented by CGP55845. In the presence of CGP55845, stimulation of MF-induced synaptic potentiation. The shift of EGABA from the depolarizing to the hyperpolarizing direction with bumetanide, a blocker of the cation-chloride co-transporter NKCC1, prevented synaptic potentiation and caused synaptic depression, suggesting that the depolarizing action of GABA observed in the presence of CGP55845 is responsible for the potentiating effect. It is proposed that, activation of GABAB receptors by spillover of GABA from MF terminals reduces the probability of release and contributes to synapses silencing. This would act as a filter to prevent excessive activation of the auto-associative CA3 network and the emergence of seizures.

Highlights

In the developing hippocampus, GABAergic signaling plays a crucial role in generating primitive patterns of network activity known as giant depolarizing potentials or GDPs (Ben-Ari et al, 2007)
We showed that early in postnatal development, GABA released from mossy fibers (MF) terminals is under the powerful control of presynaptic GABAB receptors which contribute to synapses silencing
In a recent report (Uchigashima et al, 2007), GABAergic responses evoked in CA3 principal neurons of developing mice by minimal stimulation of granule cells were attributed to GABA released from low threshold GABAergic interneurons

Summary

Introduction

GABAergic signaling plays a crucial role in generating primitive patterns of network activity known as giant depolarizing potentials or GDPs (Ben-Ari et al, 2007). GABA-induced membrane depolarization activates N-methyld-aspartate receptors and voltage-dependent calcium channels with consequent calcium rise inside the cells and activation of intracellular signaling cascades. Such mechanisms are central to the well-known trophic action of GABA which regulates several key developmental steps including DNA synthesis, cell migration, cell growth and synapse formation (Owens and Kriegstein, 2002). Evidence has been recently provided that the principal neurotransmitter released from mossy fibers (MF) during the first week of postnatal life is GABA (Safiulina et al, 2006) In adulthood, these fibers are glutamatergic and are endowed with a number of receptor types which up or down-regulate the transmitter release. It has been shown that they control network activity (McLean et al, 1996) and modulate the amplitude of glutamate- or GABA-

Methods

Results

Conclusion