Trends in Neurosciences
Volume 20, Issue 11, 1 November 1997, Pages 523-529
Journal home page for Trends in Neurosciences

GABAA, NMDA and AMPA receptors: a developmentally regulated `ménage à trois'

https://doi.org/10.1016/S0166-2236(97)01147-8Get rights and content

Abstract

The main ionotropic receptors (GABAA, NMDA and AMPA) display a sequential participation in neuronal excitation in the neonatal hippocampus. GABA, the principal inhibitory transmitter in the adult CNS, acts as an excitatory transmitter in early postnatal stage. Glutamatergic synaptic transmission is first purely NMDA-receptor based and lacks functional AMPA receptors.  Therefore, initially glutamatergic synapses are `silent' at resting membrane potential, NMDA channels being blocked by Mg2+. However, when GABA and glutamatergic synapses are coactivated during the physiological patterns of activity, GABAA receptors can facilitate the activation of NMDA receptors, playing the role conferred to AMPA receptors later on in development. Determining the mechanisms underlying the development of this `ménage à trois' will shed light not only on the wide range of trophic roles of glutamate and GABA in the developing brain, but also on the significance of the transition from neonatal to adult forms of plasticity.

Section snippets

Developmental changes in GABAergic transmission.

Functional GABAA receptors are expressed in neurones as early as embryonic stages and investigations by different groups have led to the conclusion that a transient excitatory action of GABA, via GABAA receptors, represents a general feature of the developing neurones. Activation of GABAA receptors depolarizes neuroblasts and immature neurones in all regions of the CNS studied so far, including spinal cord6, 7, 8, 9, hypothalamus[10], cerebellum[11], cortex12, 13, 14, hippocampus1, 5, 15, 16

Sequential development of NMDA and AMPA receptor-mediated glutamatergic synaptic transmission

Recent studies have also revealed that glutamatergic synaptic transmission undergoes significant changes during development. The probably major observation that has been made recently in this field is that glutamatergic transmission is initially purely NMDA receptor-mediated, without any significant contribution of AMPA receptors41, 42, 43, 44. Since the voltage-dependent Mg2+ block of NMDA channels is as efficient in neonatal hippocampal neurones as it is in adults45, 46, these premature

Synergistic excitatory actions of GABAA and NMDA receptors

In adult neurones, GABAergic inhibition prevents the activation of NMDA receptors thus inhibiting the induction of NMDA receptor-dependent forms of synaptic plasticity (60, 61, 62, but see also [22]). A different situation prevails in the neonatal brain, in which GABA provides depolarization instead of hyperpolarization. Indeed, GABAA receptor-mediated depolarization attenuates the voltage-dependent Mg2+ block of single NMDA channels recorded in cell- attached configuration from neonatal CA3

GDPs and associated [Ca2+]i oscillations

Synchronized neuronal activity and [Ca2+]i oscillations have been reported in a wide range of central and peripheral systems5, 64, 65, 66, 67, 68, 69 and appear to be a fundamental feature of developing brain structures. Although the mechanisms, including gap junctions64, 65, 70, 71 or synaptic transmission5, 66, 69, 72, involved in their generation may differ, oscillations are thought to play a central role in the development and formation of functional neuronal circuits. In embryonic spinal

Concluding remarks

The observations summarized in this review show that in an early postnatal period the hippocampal circuit shifts from one in which GABAA and NMDA receptors are the key elements to one in which AMPA and NMDA receptors act in synergy to mediate the excitatory drive (Fig. 5). Following this abrupt switch, GABAA receptors exert their inhibitory role preventing sustained excitatory and potentially excitotoxic glutamatergic activity. This general pattern is of course subject to local changes

Acknowledgements

The authors wish to thank Dr E. Cherubini for his contribution in the initial steps of these studies, and Drs G. Buszaki and K. Kaila for critical reading of the manuscript and suggestions.

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