The effects of 5-HT on memory and the hippocampus: a model and data
Meeter, Talamini, Schmitt, Riedel
Review of 5-HT receptors in the hippocampus
Serotonergic receptors are heterogeneous, and the nomenclature has long been under debate. In recent years, however, consensus has grown around a division in seven families, which will be followed here. The following discussion deals mainly with data reported in hippocampal in vitro and in vivo studies. The effects of 5-HT in this region have been organized into three categories: effects on the membrane potential of principal cells, effects on plasticity, and interactions with acetylcholine (ACh).
Location and density of 5-HT receptors in the hippocampus
5-HT innervation of the hippocampus originates from the raphe nuclei in the midbrain (Wyss et al., 1979). 5-HT is released both via varicosities into the extracellular space, and via synapses (Umbriaco et al., 1995), the latter usually being situated on the dendrites or soma of selected classes of GABA-ergic interneurons (Gulyás et al., 1999). Direct effects of 5-HT on principal cells thus occur through its release in extracellular space.
5-HT has both depolarising and hyperpolarizing effects in the hippocampus, via its different receptors. Activation of receptors from the 5-HT2 family (5-HT2A and 5-HT2C, present in all areas of the hippocampus) has been suggested to induce depolarization in principal cells in the dentate gyrus (Piguet and Galvan, 1994) and other areas of the brain (Barnes and Sharp, 1999). These depolarizing effects of 5-HT are counteracted by a direct hyperpolarization of pyramidal and granular cells in the hippocampus through 5-HT1a receptors, which are present in high density on the membranes of these cell types (Burnet et al., 1995). Another receptor that is also relatively abundant in the hippocampus is the 5-HT3 receptor (Parker et al., 1996). This receptor is present primarily on interneurons (Morales et al., 1996), and stimulates the release of GABA in the hippocampus (Piguet and Galvan, 1994), which also leads to hyperpolarization of principal cells. A similar functional path has been ascribed to 5-HT6 receptors, which are also found on hippocampal interneurons (Woolley et al., 2004). Specific 5-HT6 antagonists have been found to increase glutamate release in the hippocampus (Dawson et al., 2001).
The hyperpolarizing effects of 5-HT appear to dominate the depolarizing effects of 5-HT, as bath application hyperpolarizes granule cells in slice preparations of the dentate gyrus (Piguet and Galvan, 1994). As 5-HT1A and 5-HT3 receptors are abundant in all hippocampal layers and subregions(Burnet et al., 1995, Parker et al., 1996), hyperpolarization may be the dominant influence of 5HT everywhere in the hippocampus.
Another effect of 5-HT is the reduction of afterhyperpolarizing (AHP) currents in CA1 pyramidal cells through activation of 5-HT4 receptors (Torres et al., 1996), and in CA1 and CA3 through 5-HT7 receptors (Bacon and Beck, 2000, Tokarski et al., 2003). Although 5-HT application may thus result mainly in hyperpolarization of hippocampal principal cells, the diminution of AHP currents may increase firing to sustained depolarizing inputs (Gulyás et al., 1999), as principal cells will adapt less strongly to current in the absence of AHP.
Effects on LTP and LTD
The data on the influence of 5-HT on long-term potentiation (LTP) is fragmentary. Specific agonists of the 5-HT2A receptor have been found to enhance LTP in the hippocampus (Wang and Arvanov, 1998), and it has been speculated that 5-HT4 receptor agonists also enhance LTP (Barnes and Sharp, 1999). Agonists of the 5-HT1A receptor have been reported to specifically impair LTD, thereby increasing on balance LTP (Normann et al., 2000). On the other hand, fluvoxamine, a selective serotonin reuptake inhibitor, blocks LTP in CA1, an effect that has been related to 5-HT1A receptors (Kojima et al., 2003). Moreover, 5-HT3 antagonists can facilitate LTP, which suggests that 5-HT3 receptors may inhibit induction of LTP (Staubli and Xu, 1995). Complete abolishment of 5-HT innervation in the hippocampus increases LTP in vivo (Ohashi et al., 2003) –which would suggest that, on balance, 5-HT exerts a negative influence on LTP. It is, however, not clear whether this effect is specific to LTP, or secondary to other changes.
Interactions with ACh
Neurotransmitters do not only have effects by themselves, they can also alter the impact of other neurotransmitters. In the case of 5-HT, much attention has been given to its interactions with the cholinergic system. 5-HT4 and 5-HT-1A agonists increase ACh release, as measured by in vivo microdialysis in the hippocampus and cortex (Koyama et al., 1999, Yamaguchi et al., 1997). The same is true for at least some receptors of the 5-HT2 family (Nair and Gudelsky, 2004). On the other hand, 5-HT3 receptors inhibit ACh release in the hippocampus (Diez-Ariza et al., 2002), and the same has been suggested for 5-HT6 receptors (Woolley et al., 2004). Perhaps because of these counteractive effects, 5-HT denervation of the hippocampus does not significantly alter ACh release in slice preparations of the hippocampus (Birthelmer et al., 2003). No clear conclusions are thus possible regarding the overall effect of 5-HT on ACh release in the hippocampus. Whether or not ACh increases 5-HT release is also not clear, as nicotinergic and muscarinergic ACh receptors have opposite effects on 5-HT release (Vizi and Kiss, 1998).
Partly because of the heterogeneity of the 5-HT receptor group, the effects of 5-HT on principal cells in the hippocampus are not yet clear. In some categories, effects of different receptors have opposite directions, and may even cancel each other out. There are two areas where a clear net effect has been documented:
5-HT hyperpolarizes hippocampal principal cells directly, through 5- HT1A receptors, and indirectly, via 5-HT3 and 5-HT6 receptors on interneurons
5-HT diminishes adaptation in principal cells through a reduction of afterhyperpolarizing currents.
It may be that 5-HT, on balance, impairs LTP, but we judged support for this conjecture too uncertain to include it in our model.
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