Salient features of synaptic organisation in the cerebral cortex1

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Abstract

The neuronal and synaptic organisation of the cerebral cortex appears exceedingly complex, and the definition of a basic cortical circuit in terms of defined classes of cells and connections is necessary to facilitate progress of its analysis. During the last two decades quantitative studies of the synaptic connectivity of identified cortical neurones and their molecular dissection revealed a number of general rules that apply to all areas of cortex. In this review, first the precise location of postsynaptic GABA and glutamate receptors is examined at cortical synapses, in order to define the site of synaptic interactions. It is argued that, due to the exclusion of G protein-coupled receptors from the postsynaptic density, the presence of extrasynaptic receptors and the molecular compartmentalisation of the postsynaptic membrane, the synapse should include membrane areas beyond the membrane specialisation. Subsequently, the following organisational principles are examined:

  • 1.

    The cerebral cortex consists of: (i) a large population of principal neurones reciprocally connected to the thalamus and to each other via axon collaterals releasing excitatory amino acids, and, (ii) a smaller population of mainly local circuit GABAergic neurones.

  • 2.

    Differential reciprocal connections are also formed amongst GABAergic neurones.

  • 3.

    All extrinsic and intracortical glutamatergic pathways terminate on both the principal and the GABAergic neurones, differentially weighted according to the pathway.

  • 4.

    Synapses of multiple sets of glutamatergic and GABAergic afferents subdivide the surface of cortical neurones and are often co-aligned on the dendritic domain.

  • 5.

    A unique feature of the cortex is the GABAergic axo-axonic cell, influencing principal cells through GABAA receptors at synapses located exclusively on the axon initial segment.

The analysis of these salient features of connectivity has revealed a remarkably selective array of connections, yet a highly adaptable design of the basic circuit emerges when comparisons are made between cortical areas or layers. The basic circuit is most obvious in the hippocampus where a relatively homogeneous set of spatially aligned principal cells allows an easy visualization of the organisational rules. Those principles which have been examined in the isocortex proved to be identical or very similar. In the isocortex, the basic circuit, scaled to specific requirements, is repeated in each layer. As multiple sets of output neurones evolved, requiring subtly different needs for their inputs, the basic circuit may be superimposed several times in the same layer. Tangential intralaminar connections in both the hippocampus and isocortex also connect output neurones with similar properties, as best seen in the patchy connections in the isocortex. The additional radial superposition of several laminae of distinct sets of output neurones, each representing and supported by its basic circuit, requires a co-ordination of their activity that is mediated by highly selective interlaminar connections, involving both the GABAergic and the excitatory amino acid releasing neurones. The remarkable specificity in the geometry of cells and the selectivity in placement of neurotransmitter receptors and synapses on their surface, strongly suggest a predominant role for time in the coding of information, but this does not exclude an important role also for the rate of action potential discharge in cortical representation of information.

Introduction

In the mammalian brain, the cerebral cortex is the largest structure as defined on the basis of a uniform cellular organisation. The two major classes of cortical cells, the generally densely spiny pyramidal cells, that release excitatory amino acid(s) as transmitter, and the generally smooth dendritic GABAergic cells receive on average 4–6000 synapses, which is not remarkable in the brain. About every fifth neurone and every sixth synaptic bouton synthesises and releases GABA; most of the rest use excitatory amino acids as transmitter 8, 7, 34. The great evolutionary success and versatility of the cerebral cortex can be explained by a design which enables the connections to respond to specific localised needs, apparent in the many selective modifications that are manifested in the great variety of neuronal subclasses of the two major cell families. The flexibility of design is also well illustrated by the wide range in the number of synapses, from a few hundred to about 30 000, received by single neurones of distinct types.

The cell type specific adaptations to local processing needs have made the definition of the basic cortical processing circuit and the definition of specific roles for particular synaptic links a daunting task. Nevertheless, although the subclasses of neurone reflect distinct synaptic connections, some basic rules of synaptic connectivity that are a hallmark of the cerebral cortex can be delineated. We consider the salient features to be the following:

  • 1.

    The cerebral cortex consists of: (i) a large population of output (principal) neurones reciprocally connected to the thalamus and to each other via axon collaterals releasing excitatory amino acids, and, (ii) a smaller population of mainly local circuit GABAergic neurones.

  • 2.

    Differential reciprocal connections are also formed amongst GABAergic neurones.

  • 3.

    All extrinsic and intracortical glutamatergic pathways terminate on both the principal and the GABAergic neurones, differentially weighted according to the pathway.

  • 4.

    Synapses of multiple sets of glutamatergic and GABAergic afferents subdivide the surface of cortical neurones and are often co-aligned on the dendritic domain.

  • 5.

    A unique feature is the GABAergic axo-axonic cell influencing principal cells through GABAA receptors at synapses located exclusively on the axon initial segment.

Below, we will examine these characteristics from high resolution studies of synaptic organisation in both the isocortex (for definition see [48]) and the hippocampal cortex. The latter has been particularly useful in revealing basic principles, due to the arrangement of the cell bodies of principal cells into a single layer, resulting in the spatial co-alignment of functionally equivalent parts of neurones. In the isocortex the cells are radially scattered, and functionally non-equivalent parts of neurones, such as distal and proximal dendrites from different types of cells, are next to one another. Furthermore, the basic cortical circuit is superimposed in the same space several times, therefore it is much more difficult to decipher from the distribution of neuronal processes which axonal and dendritic populations form synaptic relationships. Before examining the salient rules of cortical connectivity a delineation of the synapse is needed. Since the analysis of cortical connections is often still limited to the anatomically defined synapse, as revealed by electron microscopy, it is worth investigating briefly how the synapse can be defined in those molecular terms that are most relevant to its function.

Section snippets

Molecular dissection of cortical synapses

Sherrington [103]used the term synapse to express the functional effect of the axon of one neurone on the dendrites of another, but the precise membrane area responsible for this effect is not well defined. With the electron microscopic identification of membrane specialisations in the presynaptic terminal and the postsynaptic dendrite the synapse came to be considered equivalent to the area of membrane specialisation [94].

For the presynaptic terminal, the site of vesicle accumulation at the

Strength and some dynamic properties of cortical synaptic connections

In addition to the neurotransmitter mechanism, out of the many factors influencing the properties of synaptic connections between two neurones, the number and location of synaptic transmitter release sites were amongst the first recognised [24]. In the cortical network where usually connections of a large number of different cell classes overlap in space, the intuitive classification of cell types on the basis of the difference in their inputs, as reflected in the pattern of their dendrites,

Conclusions

The analysis of the salient features of cortical synaptic connections has revealed a remarkably selective array of connections (Fig. 10). Yet, a highly adaptable design of the basic circuit emerges, when comparisons are made between cortical areas. The basic circuit is best seen in the hippocampus, where a relatively homogeneous set of spatially aligned principal cells allows an easy visualization of the organisational rules. Those principles which have been examined proved to be identical or

Acknowledgements

The authors thank Dr. Ole Paulsen for his comments on an earlier version of the manuscript. G.T. was supported by the European Blaschko Visiting Scholarship during the preparation of this paper. E.H.B. holds a Medical Research Fellowship at Corpus Christi College, Oxford. Some of the work reported here has been supported by the European Community Grant BIO4-CT96-0585.

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