INMED/TINS special issue
The dual glutamatergic–GABAergic phenotype of hippocampal granule cells

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Markers of the glutamatergic and GABAergic phenotypes coexist in developing hippocampal granule cells, and activation of these neurons produces simultaneous glutamate-receptor-mediated and GABA-receptor-mediated responses in their postsynaptic cells. In the adult, markers of the GABAergic phenotype and the consequent GABAergic transmission disappear but can be transiently expressed in an activity-dependent manner. Coexistence of glutamate and GABA in neurons from other regions of the brain is being discovered, and the possibility of these neurotransmitters being co-released gives the CNS a powerful computational tool. Although waiting to be confirmed by paired recordings, the hypothesis that glutamate and GABA are co-released from single cells is a valuable heuristic proposal in understanding the plasticity inherent to neuronal communication.

Introduction

Fast chemical communication between CNS neurons is primarily conveyed by the synaptic release of two amino acids: glutamate for excitatory synaptic transmission and GABA for inhibitory synaptic transmission (although GABA can be depolarizing under certain circumstances). Almost all neurons possess a variety of receptors for different neurotransmitters, and GABA receptors are the most widely expressed. Thus, cells that are excited by glutamate can also be inhibited (or excited) by GABA, because the receptors for both neurotransmitters are present in the postsynaptic cell membrane. However, the opposite possibility, that a single presynaptic cell releases glutamate and GABA, has long been regarded as heretic. This view could have originated from the transformation of Dale's postulate that a neuron functions as a metabolic unity (whereby a process in a cell can influence all the processes of the same neuron) to a principle stating that ‘a single cell releases only one neurotransmitter’.

It is now clear that ‘one neuron – one neurotransmitter’ is the exception rather than the rule. The co-release of a fast-acting ‘classical’ neurotransmitter with peptides, ATP, Zn2+, neurotrophic factors, nitric oxide or other modulators has been established. In all these cases, the co-released factors are synthesized in the cell, are released in a selectively modulated fashion, act on receptors and are removed by specific mechanisms. These characteristics confer on them the status of neurotransmitters, albeit modulatory ones. But what about the coexistence of two fast-acting (‘classical’) neurotransmitters in the same neuron? With examples of their co-release gathering, this question is now being answered 1, 2, 3, 4, 5.

Section snippets

‘Glutamatergic’ granule cells are also ‘GABAergic’ cells

Evidence of simultaneous release of the fast acting neurotransmitters par excellence, glutamate and GABA, from the granule cell mossy fiber (MF) synapse has been accumulating. Granule cells of the dentate gyrus have been considered to form glutamatergic excitatory synapses onto pyramidal cells and local inhibitory interneurons of the CA3 hippocampus 6, 7 (Figure 1a). Thus, activation of the MF provokes monosynaptic excitatory responses in both cell types, and the activation of interneurons, in

Are there GABAA receptors apposed to MF terminals?

Previous evidence from culture preparations has shown that GABAA and AMPA receptors can cluster in a single hippocampal pyramidal cell in apposition to different terminals of the same glutamatergic fiber [31]. This suggests that the ‘mismatching’ of glutamatergic and GABAergic elements reflects a common signal involved in the alignment of presynaptic and postsynaptic components during formation of excitatory and inhibitory synapses [31]. Interestingly, excitatory nicotinic ACh receptors and

Functional implications for glutamate–GABA simultaneous transmission

Together, the available evidence suggests that the simultaneous release of glutamate and GABA from the MF could have a trophic function during development and, in the adult, could be a mechanism to counteract or prevent enhancement of excitability in the hippocampus proper, especially after seizures [28] (Box 1). At early ages, GABAergic input is needed for glutamate receptors to activate [33], suggesting that coexpression of the glutamatergic and GABAergic phenotypes in a single pathway

Are there more neurons with a dual GABAergic–glutamatergic phenotype?

Besides the hippocampal granule cells, other neurons have a functional dual glutamatergic–GABAergic phenotype. They are: granule cells of the olfactory bulb [40]; neurons of the anteroventral periventricular nucleus of the hypothalamus [41]; some neurons of the medial vestibular nucleus [42]; and neurons of the medial nucleus of the trapezoid body [35]. These trapezoid body neurons, like hippocampal granule cells [24], transiently express this dual phenotype to provide synapse-specific

Open questions

The list of questions arising from the available data on this topic is, undoubtedly, enormous. Box 2 contains some examples, and the following are questions for which answers are needed particularly urgently.

(i) Are glutamate and GABA truly co-released from a single MF? The morphological evidence that GABA can be exocytosed at MF synapses to act on postsynaptic GABAA receptors is as strong as that indicating that glutamate is released. However, the available electrophysiological evidence,

Final remarks

The mechanistic definition of a transmitter, which labels a certain neuron as glutamatergic or GABAergic, fully applies to glutamatergic–GABAergic granule cells. The transmitters that these cells use are synthesized, stored and released during nerve activity. Then they interact with specific receptors on the postsynaptic membrane that lead to changes in postsynaptic activity. However, the glutamatergic and the GABAergic responses provoked in CA3 cells and hilar neurons by granule cell

Acknowledgements

I thank the collaborators whose data contributed to this review. Research in my laboratory has been funded by Consejo Nacional de Ciencia y Tecnología, the Third World Academy of Sciences, the Alexander von Humboldt Foundation and Fundación Miguel Alemán, A.C.

References (48)

  • A. Semyanov

    Tonically active GABAA receptors: modulating gain and maintaining the tone

    Trends Neurosci.

    (2004)
  • V. Gundersen

    GABAergic synapses in hippocampus exocytose aspartate on to NMDA receptors: quantitative immunogold evidence for co-transmission

    Mol. Cell. Neurosci.

    (2004)
  • S. Ebihara

    Mouse vesicular GABA transporter gene: genomic organization, transcriptional regulation and chromosomal localization

    Mol. Brain Res.

    (2003)
  • P. Jonas

    Corelease of two fast neurotransmitters at a central synapse

    Science

    (1998)
  • Y.H. Jo et al.

    Synaptic corelease of ATP and GABA in cultured spinal neurons

    Nat. Neurosci.

    (1999)
  • D. Sulzer et al.

    Dale's principle and glutamate corelease from ventral midbrain dopamine neurons

    Amino Acids

    (2000)
  • B. Yang

    A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor

    Nat. Neurosci.

    (2002)
  • W-C. Li

    Glutamate and acetylcholine corelease at developing synapses

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • I.L. Crawford et al.

    Localization and release of glutamic acid in relation to the hippocampal mossy fibre pathway

    Nature

    (1973)
  • L. Acsády

    GABAergic cells are the major postsynaptic targets of mossy fibers in the hippocampus

    J. Neurosci.

    (1998)
  • R. Sandler et al.

    Coexistence of GABA and glutamate in mossy fiber terminals of the primate hippocampus: an ultrastructural study

    J. Comp. Neurol.

    (1991)
  • R.S. Sloviter

    Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus

    J. Comp. Neurol.

    (1996)
  • I. Mody

    The GAD-given right of dentate gyrus granule cells to become GABAergic

    Epilepsy Curr.

    (2002)
  • R. Gutiérrez

    Seizures induce simultaneous GABAergic and glutamatergic neurotransmission in the dentate gyrus–CA3 system

    J. Neurophysiol.

    (2000)
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