Review
Structural basis of the cholinergic and serotonergic modulation of GABAergic neurons in the hippocampus

https://doi.org/10.1016/S0197-0186(99)00041-8Get rights and content

Abstract

Ascending subcortical pathways effectively modulate hippocampal information processing. Two components, the cholinergic and serotonergic pathways have been demonstrated to play an important role in the generation of behaviour-dependent hippocampal EEG patterns. Several findings suggest that the above projections influence the activity of hippocampal interneurons. Here we review the available data from physiological, pharmacological and receptor localization experiments, drawing attention to the crucial role of interneurons in the transfer and amplification of subcortical effects on cortical information processing. We hypothesize that, by exerting diverse actions on different subsets of interneurons, the cholinergic and serotonergic systems might change the balance of somatic and dendritic inhibition, and consequently change the integrative properties of hippocampal principal cells.

Introduction

The hippocampus has been shown to be involved in the integration of information arriving from different sensory and associational cortical areas as well as in the formation of various types of memory traces. Hippocampal electrical activity is characterized by different behaviour-dependent EEG patterns (Buzsáki et al., 1983, Vanderwolf, 1988), which are shaped by afferent systems carrying information from two major sources. From the entorhinal cortex numerous perforant path fibres relay specific sensory cortical information about the environment. In contrast, information about the motivational, emotional and autonomic state of the animal arrives via subcortical pathways, which are numerically sparse, originate from the nuclei containing only a few thousand of neurons. Two major components of these projections are the subjects of this review, the serotonergic pathway arising from the raphe nuclei (Azmitia and Segal, 1978a, Azmitia and Segal, 1978b, Kosofsky and Molliver, 1987, Tohyama et al., 1980) and the cholinergic projection originating from the medial septum (Mesulam et al., 1983, Wainer et al., 1985). The question arises how these relatively sparse projections are able to robustly influence the activity pattern of the hippocampus and other cortical areas. Based on electrophysiological, pharmacological and anatomical experiments we propose that these subcortical afferents achieve their great efficacy by the modulation of GABA-containing interneurons. Since each of these interneurons innervate several thousand pyramidal cells, control of the small number of GABAergic neurons allows a global modulation of hippocampal activity.

Although the interneuron/principal cell ratio in the hippocampus is only 1:10–1:12 (Woodson et al., 1989), interneurons have a much higher structural and functional diversity than pyramidal or granule cells (Freund and Buzsáki, 1996). Hippocampal interneurons are all GABAergic and inhibitory in simple terms. Their diversity is manifested in their anatomical, neurochemical, electrophysiological and pharmacological properties (for review see Freund and Buzsáki, 1996).

Strong correlation has been established between the anatomical properties and neurochemical marker content of different interneuron populations. Inhibitory cells having axonal arbors with specific laminar distributions and terminating on well-defined parts of principal cells or interneurons (Gulyás et al., 1993a; Han et al., 1993), mediate functionally different inhibition (Miles et al., 1996), and express different calcium binding proteins or neuropeptides (Acsády et al., 1996a, Gulyás et al., 1991, Deller and Léránth, 1990, Gulyás and Freund, 1996, Gulyás et al., 1996, Katona et al., 1998, Kosaka et al., 1987, Kosaka et al., 1985). The best characterized class of interneurons is the group of perisomatic inhibitory cells that include basket and axo-axonic cells. Perisomatic inhibition plays an important role in the control of Na-spike generation, i.e. the output of the innervated neurons (Miles et al., 1996). Axo-axonic cells and a portion of basket cells were shown to contain PV (Kosaka et al., 1987), while another group of basket cells contains both CCK and VIP (Acsády et al., 1996b). A second class of inhibitory cells terminates on the dendrites of pyramidal cells in str. radiatum, lacunosum-moleculare and oriens. Dendritic inhibition controls the generation of dendritic Ca2+ spikes, and the activation of NMDA receptors of glutamatergic synapses on dendrites. Since dendritic free Ca2+ levels, and NMDA receptor activation are required for long term potentiation (LTP), inhibition in the dendritic region may effectively control synaptic plasticity. Interneurons with axons arborizing in the dendritic region where Schaffer collaterals terminate are immunoreactive for calbindin D28k (Gulyás and Freund, 1996), whereas interneurons innervating the entorhinal recipient layers contain somatostatin (Katona et al., 1998). These latter cells have horizontally running dendrites in str. oriens of the CA1–3 regions and in the hilus of the dentate gyrus and are covered by long branching spines. The third class of interneurons have a unique target selectivity and were revealed by immunostaining against calretinin and VIP (Acsády et al., 1996b, Gulyás et al., 1996). These cells selectively innervated other interneurons and, in addition, often formed dendro-dendritically and axo-dendritically coupled networks.

Interneurons are unique in terms of their sensitivity to subcortical modulatory transmitters. First of all, their response to the application of 5HT, noradrenaline, acetylcholine and other transmitters is different from that of pyramidal cells (see below). Second, in contrast to principal cells which show rather uniform response properties, the response repertoire of interneurons is more diverse (Parra et al., 1998). The possible reason for this is that interneurons express a different set of transmitter receptors compared to principal cells (for review see Freund and Buzsáki, 1996).

The first evidence that interneurons are selectively involved in mediating the subcortical control of hippocampal activity came from the anatomical study of the GABAergic septohippocampal pathway, where Freund and Antal (1988) demonstrated that this pathway selectively terminates on interneurons. Following this observation numerous other studies revealed that interneurons are in a key position to relay subcortical information (for review see Freund and Buzsáki, 1996).

This review will summarize data and hypotheses about the possible roles of cholinergic and serotonergic pathways in the control of hippocampal electrical activity via interneurons.

Section snippets

Cholinergic control of hippocampal neurons

The cholinergic modulation of hippocampal excitability has been described almost two decades ago (Krnjevic et al., 1981). The cholinergic septohippocampal pathway was shown to exert its effects in several ways, and to play an important role in the generation of hippocampal theta activity (Kramis et al., 1975). Both a direct depolarization of principal cells, as well as a reduction of the potency of inhibition was demonstrated in vivo (Ben-Ari et al., 1981) and in vitro (Haas, 1982). Subsequent

Serotonergic innervation of the hippocampus

The hippocampal formation is densely innervated by serotonin-containing fibres that originate in the midbrain raphe nuclei (Lidov et al., 1980, Wyss et al., 1979). Many of the projecting neurons are situated in the median raphe nucleus and their axons reach the hippocampus via two separate routes (Azmitia and Segal, 1978b, Moore et al., 1978). Infracallosal serotonergic fibres enter the hippocampus from rostral directions through the fimbria and the dorsal fornix, while supracallosal axons run

Summary

Anatomical and electrophysiological studies demonstrated that GABAergic neurons are in a key position to convey subcortical information carried by cholinergic and serotonergic afferents to the hippocampus, critically influencing network activity. Various interneuron types and inhibitory processes are differentially affected by these neurotransmitters. However, apparently the two subcortical transmitters modify GABAergic mechanisms in opposite directions.

Acetylcholine increases the activity of

Acknowledgements

This work was supported by the Human Frontier Science Program Organization, the Howard Hughes Medical Institute, the McDonnell Foundation and OTKA (T16942, T23261, F17119), Hungary.

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