Interneurons set the tune of developing networks

doi:10.1016/j.tins.2004.05.002

Trends in Neurosciences

Volume 27, Issue 7, 1 July 2004, Pages 422-427

https://doi.org/10.1016/j.tins.2004.05.002 Get rights and content

Abstract

Despite a rather long migratory journey, interneurons are functional before vertically migrating pyramidal neurons and they constitute the source and target of the first functional synapses in the developing hippocampus. Interneuron-driven network patterns are already present in utero while principal cells are mostly quiescent. At that early stage, GABAergic synapses – which are formed before glutamatergic ones – are excitatory, suggesting that GABA is a pioneer, much like the neurons from which it is released. This review discusses this sequence of events, its functional significance and the role that interneurons might play in the construction of cortical networks.

Section snippets

Different source and different journeys

GABAergic interneurons in rodents originate essentially in the ganglionic eminences and enter the developing cortex via a tangential migration [5] that appears not to require a glial scaffold. In humans [6] and non-human primates (Z. Petanjek et al., unpublished), interneurons also originate in the subventricular zone, suggesting interesting evolutionary changes in the development of the cortical mantle. By contrast, pyramidal neurons are generated near the surface of the cerebral ventricle [7]

GABAergic synapses are established before glutamatergic ones on interneurons and principal cells

Studies using selective glutamate and GABA receptor antagonists suggest that GABA receptors and synapses are operative before glutamatergic synapses in all brain structures and species studied to date 16, 17, 18 (see also references in Ref. [4]). This sequence was demonstrated more directly in studies in which hippocampal neurons were patch-clamp recorded from the CA1 region of hippocampal slices obtained in utero and at birth 19, 20. The synaptic activity of both interneurons and pyramidal

GABAergic synapses are formed first on apical dendrites

Studies using synapsin and glutamate decarboxylase (GAD) immunoreactivity suggest that the first synapses on pyramidal neurons are probably made on the apical dendrites and not on the soma [19] (Figure 1c,d) and are GABAergic [14]. In fact, ‘silent’ pyramidal cells – those with no synaptic activity – have no apical dendrites, suggesting that synapses are formed only once pyramidal neurons have extended apical dendrites 19, 20. In keeping with this, dendritic projecting interneurons such as

Interneurons supply initially most of the activity

A comparative analysis of the morphological–functional maturation of interneurons and pyramidal cells reveals that the former mature before the latter, despite a similar GABA–glutamate sequence [20]. Thus, at rat embryonic day (E)18–E20, 12% of pyramidal neurons and 65% of interneurons had functional synapses [20]. A similar ratio is found at birth 19, 20. If the first functional synapses are between interneurons, the initial patterns recorded will be generated primarily, if not solely, by

GABA excites at early developmental stages

Studies performed in the hippocampus suggest that immature neurons have a higher intracellular Cl⁻ concentration, leading to depolarization by GABA of immature neurons [28], generation of action potentials 23, 29, 30, activation of NMDA receptors [29] and a rise of intracellular Ca²⁺ concentration [31]. These properties are not limited to hippocampal neurons, because they are found in a wide range of brain structures and species [4].

The K⁺–Cl⁻ cotransporter 2 (KCC2), which usually extrudes Cl⁻

Discussion

In conclusion, these observations suggest that the operation of GABAergic synapses is a key mechanism in the development of cortical networks. The heterogeneity of interneurons, with its endowed capacity to control a wide range of selective actions, is highly suitable to begin the sequence of events required for the shift from an ensemble of immature neurons that communicate via primitive paracrine systems (Box 1) to one that operates via synapses.

The first synapses are GABAergic; they occur

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Citation Excerpt :
Furthermore, while GABA is an inhibitory neurotransmitter in the adult brain, at early stages of fetal development it acts as an excitatory neurotransmitter due to the high intracellular chloride ion (Cl−) concentration of the immature post-synaptic neuron (Ben-Ari et al., 1989), leading to the generation of action-potentials (Tyzio et al., 2003). As a result, most of the initial activity recorded is generated by the interneurons that use excitatory GABA as a neurotransmitter, while most of the pyramidal cells are silent (Ben-Ari et al., 2004). In order to detect and amplify the small magnetic fields generated by neural activity of the brain, Superconducting Quantum Interference Device (SQUID) technology is used (Cohen, 1972; Hamalainen et al., 1993).
Early brain development, from the embryonic period to infancy, is characterized by rapid structural and functional changes. These changes can be studied using structural and physiological neuroimaging methods. In order to optimally acquire and accurately interpret this data, concepts from adult neuroimaging cannot be directly transferred. Instead, one must have a basic understanding of fetal and neonatal structural and physiological brain development, and the important modulators of this process. Here, we first review the major developmental milestones of transient cerebral structures and structural connectivity (axonal connectivity) followed by a summary of the contributions from ex vivo and in vivo MRI. Next, we discuss the basic biology of neuronal circuitry development (synaptic connectivity, i.e. ensemble of direct chemical and electrical connections between neurons), physiology of neurovascular coupling, baseline metabolic needs of the fetus and the infant, and functional connectivity (defined as statistical dependence of low-frequency spontaneous fluctuations seen with functional magnetic resonance imaging (fMRI)). The complementary roles of magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS) are discussed. We include a section on modulators of brain development where we focus on the placenta and emerging placental MRI approaches. In each section we discuss key technical limitations of the imaging modalities and some of the limitations arising due to the biology of the system. Although neuroimaging approaches have contributed significantly to our understanding of early brain development, there is much yet to be done and a dire need for technical innovations and scientific discoveries to realize the future potential of early fetal and infant interventions to avert long term disease.

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Trends in Neurosciences

Interneurons set the tune of developing networks

Abstract

Section snippets

Different source and different journeys

GABAergic synapses are established before glutamatergic ones on interneurons and principal cells

GABAergic synapses are formed first on apical dendrites

Interneurons supply initially most of the activity

GABA excites at early developmental stages

Discussion

Trends Neurosci

Trends Neurosci

Trends Neurosci

Trends Neurosci

Trends Neurosci

Brain Res

Brain Res

Brain Res. Dev. Brain Res

Neurosci. Lett

Neuroscience

Neuroscience

Neuron

Cell

Trends Neurosci

Neurosci. Lett

Neurosci. Res

Neuron

Neuron

Excitatory actions of GABA during development: the nature of the nurture

Nat. Rev. Neurosci

A long, remarkable journey: tangential migration in the telencephalon

Nat. Rev. Neurosci

Origin of GABAergic neurons in the human neocortex

Nature

Autoradiographic study of cell migration during histogenesis of cerebral cortex of the mouse

Nature

Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in Macacus Rhesus

J. Comp. Neurol

Prominent expression of two forms of glutamate decarboxylase in the embryonic and early postnatal rat hippocampal formation

J. Neurosci

Multimodal tangential migration of neocortical GABAergic neurons independent of GPI-anchored proteins

Development