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Development of GABA innervation in the cerebral and cerebellar cortices

Key Points

  • In many areas of the vertebrate brain, GABAergic interneurons are crucial in the organization and function of neural circuits. The spatial and temporal dynamics of inhibition are achieved by diverse types of interneurons which have distinct morphology, physiological properties, connectivity patterns and gene expression profiles.

  • Different classes of interneurons display characteristic axon arbors and innervation patterns, and these distribute their inhibitory outputs to discrete spatial locations, cell types and subcellular compartments within the network. GABAergic synapses are also modified by usage, leading to reconfiguration of the inhibitory circuits by experience. The cellular and molecular mechanisms that specify and modify inhibitory innervation patterns are only just beginning to be understood.

  • Neocortical interneurons have common as well as distinct features in their axon arbor geometry, branching patterns, bouton distribution and arrangement; some of these features, including subcellular synapse organization, are preserved in organotypic cultures, suggesting that they are largely determined by genetic mechanisms.

  • A prominent feature of GABAergic innervation is the targeting of different classes of inhibitory synapse to subcellular compartments of principal neurons. The subcellular organization of inhibitory synapses is superimposed on the intrinsic biophysical compartmental architecture of principal neurons, and is essential in regulating input integration, spike probability, timing and back propagation.

  • In the cerebellum, the subcellular distribution of neurofascin (a member of the L1 family immunoglobulin cell adhesion molecules (L1CAMs) that is recruited by the membrane cytoskeleton protein AnkyrinG) directs GABAergic innervation to the axon initial segment of Purkinje neurons. GABAergic innervation of Purkinje dendrites is guided by an intermediate scaffold of Bergmann glia fibers, and it requires another member of the L1CAM family, CHL1 (close homologue of L1) to act as a molecular signal.

  • GABAergic interneurons in the neocortex often display exuberant local innervation of hundreds of target neurons, with dense and clustered synapses on each target. The maturation of perisomatic innervation by basket interneurons in the visual cortex proceeds into adolescence and is regulated by neural activity and visual experience.

  • GABA and GAD67 act beyond their classic roles in inhibitory transmission. They also regulate the activity-dependent morphogenesis of GABAergic axons and synapses, and thus regulate the innervation field of interneurons in the adolescent neocortex.

  • Technical advances in two areas will significantly accelerate progress in studying the development of GABA innervation: efficient and high-resolution labelling of different classes of GABAergic axons and synapses, and systematic molecular and genetic perturbation of the development of GABA interneurons.

Abstract

In many areas of the vertebrate brain, such as the cerebral and cerebellar cortices, neural circuits rely on inhibition mediated by GABA (γ-aminobutyric acid) to shape the spatiotemporal patterns of electrical signalling. The richness and subtlety of inhibition are achieved by diverse classes of interneurons that are endowed with distinct physiological properties. In addition, the axons of interneurons display highly characteristic and class-specific geometry and innervation patterns, and thereby distribute their output to discrete spatial domains, cell types and subcellular compartments in neural networks. The cellular and molecular mechanisms that specify and modify inhibitory innervation patterns are only just beginning to be understood.

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Figure 1: Axon arbors and innervation patterns of neocortical interneurons.
Figure 2: The subcellular organization of GABAergic inputs.
Figure 3: Mechanisms of subcellular targeting of GABAergic synapses along cerebellar Purkinje neurons.
Figure 4: The experience-dependent maturation and plasticity of perisomatic innervation by basket interneurons in the neocortex.
Figure 5: GAD67 and GABA signalling regulate the maturation of perisomatic innervation.
Figure 6: Activity-dependent GABA synthesis and signalling regulate the maturation and plasticity of the inhibitory innervation field.

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Acknowledgements

The work carried out by the author's laboratory is supported by the US National Institutes of Health and the March of Dimes Birth Deficit Foundation. Z.J.H. is a McKnight, Pew, and EJLB scholar. G.D. is a European Molecular Biology Organization long-term fellow and has a NARSAD Young Investigator Award from the Forrest C. Lattner Foundation. F.A. is supported by a postdoctoral fellowship from the Human Frontier Science Program.

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Glossary

Principal neurons

Neurons that usually project their axons far away from their somata, in contrast to local circuit neurons or interneurons.

Homeobox code

The combinatorial expression of a set of homeodomain transcription factors in distinct spatial domains of the developing nervous system which governs the specification of neuronal cell types.

Potential synapse

The close apposition between axons and dendrites that is necessary to form an actual synapse.

Regenerative sodium spike

A regenerative action potential that is triggered by the opening of sodium channels in neuronal axons (often at the axon initial segment) and that propagates to axon terminals and triggers transmitter release. They also back-propagate towards dendrites and influence neuronal excitability and plasticity.

Axon initial segment

(AIS). The area of the axon near the soma that contains a high density of voltage-gated sodium channels, which are responsible for the initial depolarization that leads to the initiation of the action potential.

Tenascin-R

(TNR). An extracellular matix protein that is expressed primarily in the CNS in distinct tissues at different times during embryonic development and in adults. It is a member of the tenascin (TN) gene family, which includes at least three genes in mammals.

Candidate gene approach

In contrast to a genetic screen, which is largely unbiased and makes no assumptions of the underlying mechanisms and genes that are involved in a biological process, the candidate gene approach tests the role of specific genes based on prior knowledge.

RNA interference

(RNAi). A mechanism for RNA-guided regulation of gene expression, in which double-stranded ribonucleic acid inhibits the expression of genes with complementary nucleotide sequences. The RNAi pathway, which is conserved in most eukaryotic organisms, is thought to have evolved as a form of innate immunity against viruses, and it also has a major role in regulating development and genome maintenance.

Single nucleotide polymorphism

(SNP). The most common form of variation in human DNA sequences. It occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).

Rett syndrome

A childhood neurodevelopmental disorder that almost exclusively affects females. It is caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene.

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Huang, Z., Di Cristo, G. & Ango, F. Development of GABA innervation in the cerebral and cerebellar cortices. Nat Rev Neurosci 8, 673–686 (2007). https://doi.org/10.1038/nrn2188

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