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  • Review Article
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Laminating the hippocampus

Nature Reviews Neuroscience volume 7, pages 259–268 (2006)Cite this article

Key Points

  • A characteristic feature of the hippocampus is its lamination of neuronal cell bodies and afferent fibre projections. This review summarizes recent studies on the molecular determinants that govern the formation of hippocampal cell and fibre layers.

  • Initial experiments using sequential slice co-cultures ruled out temporal factors in the layer-specific termination of afferent projections to the dentate gyrus.

  • Afferent fibres from the entorhinal cortex are guided to the dentate gyrus by axons of pioneer neurons (Cajal–Retzius cells). By contrast, commissural/associational fibres to the dentate gyrus do not require pioneer neurons. They are guided to the inner molecular layer by positional cues on proximal segments of granule cell dendrites.

  • The layer-specific termination of entorhinal axons in the outer molecular layer of the dentate gyrus is controlled by the extracellular matrix molecule hyaluronan. The lamination of granule cells is under the control of the extracellular matrix protein reelin.

  • In the marginal zone of the dentate gyrus, reelin is a positional signal for the extension and orientation of radial glial fibres. A regular radial glial scaffold is necessary for the directed migration of granule cells. Reelin also acts as a stop signal for migrating granule cells, preventing them from invading the molecular layer.

  • A laminated dentate gyrus is required for the proper function of the hippocampus. Temporal lobe epilepsy is associated with a loss of granule cell lamination (granule cell dispersion) and decreased reelin expression. Decreased reelin expression associated with granule cell dispersion in epilepsy suggests that reelin controls granule cell lamination not only during development, but throughout postnatal life.

Abstract

Lamination of neurons and fibre projections is a fundamental organizational principle of the mammalian cerebral cortex. A laminated organization is likely to be essential for cortical function, as studies in mutant mice have revealed causal relationships between lamination defects and functional deficits. Unveiling the determinants of the laminated cortical architecture will contribute to our understanding of how cortical functions have evolved in phylogenetic and ontogenetic development. Recently, the hippocampus, with its clearly segregated cell and fibre layers, has become a major subject of studies on cortical lamination.

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Figure 1: The laminated structure of the hippocampus.
Figure 2: Different signals control the laminated termination of entorhinal and commissural/associational fibres to the dentate gyrus.
Figure 3: Rescue of granule cell lamination in the reeler dentate gyrus.

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Acknowledgements

We thank S. Dieni for her helpful comments on the manuscript. Our work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation).

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Authors and Affiliations

  1. Department of Neuroanatomy, Institute of Anatomy and Cell Biology, University of Freiburg, Albertstrasse 17, Freiburg, D-79104, Germany

    Eckart Förster, Shanting Zhao & Michael Frotscher

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  1. Eckart Förster
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  2. Shanting Zhao
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Correspondence to Michael Frotscher.

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FURTHER INFORMATION

Institute of Anatomy and Cell Biology

Glossary

Principal neurons

A term that describes glutamatergic hippocampal pyramidal neurons and dentate granule cells that outnumber GABAergic interneurons.

Organotypic slice culture

A culture system that preserves the environment of the cultured cells, as tissue sections and not dissociated cells are cultivated.

Cajal–Retzius cell

A type of early-generated neuron that populates the marginal zone of the cerebral cortex. Originally described by Gustaf Retzius and Santiago Ramn y Cajal, these cells were recently found to synthesize and secrete the glycoprotein reelin. Reelin is important for the proper migration of cortical neurons.

Radial glia

A type of glial cell that gives rise to long, radially oriented processes. These processes provide a scaffold for radially migrating neurons. Recent studies have shown that radial glial cells are neuronal precursors.

Suprapyramidal blade

Describes the part of the granule cell layer that is close to hippocampal area CA1, and is located above the pyramidal cell layer in CA3.

Infrapyramidal blade

Describes the part of the granule cell layer that is furthestfrom CA1, and is located underneath the pyramidal cell layer in CA3.

Ganglionic eminence

A ventral portion of the telencephalic vesicle. It is a source of GABAergic interneurons destined for the neocortex and hippocampus, and is the anlage of the future striatum.

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Förster, E., Zhao, S. & Frotscher, M. Laminating the hippocampus. Nat Rev Neurosci 7, 259–268 (2006). https://doi.org/10.1038/nrn1882

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