Effects of 5-HT on Memory and the Hippocampus: Model and Data

Abstract

5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT 1A and 5-HT 3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT 1A agonists ameliorate memory deficits in depression. INTRODUCTIONHypofunction of the 5-hydroxytryptamine (5-HT) system has emerged as a leading candidate cause for depression (Naughton et al, 2000;Middlemiss et al, 2002). At the same time, several lines of evidence point to a role for 5-HT in memory (Buhot et al, 2000). Most prominently, depletion of tryptophan (TRP), a precursor of 5-HT, is associated with lower performance on episodic memory retention tests in humans (Riedel et al, 1999). This mirrors findings in depression, which is accompanied by moderate to severe memory deficits (Johnson and Magaro, 1987;Schaub et al, 2003). However, manipulations that increase 5-HT concentration or 5-HT receptor activation also lower memory performance, as indicated by receptor agonist studies in both humans (Riedel et al, 2002) and animals (Altman and Normile, 1988). Up to now, it is not known why both increased and decreased 5-HT activation have adverse effects on memory.5-HT binds to a large and disparate family of CNS receptors, which have effects that are sometimes opposite. Thus, many effects of different receptors seem to cancel each other out. In a review (see Supplementary Information on internet), we identify two robust effects of 5-HT in the hippocampus. First, 5-HT exerts a hyperpolarizing influence on principal cells; directly, via 5-HT 1A receptors, and indirectly, via facilitation of GABA release from local interneurons through 5-HT 3 receptors (Burnet et al, 1995;Piguet and Galvan, 1994). Activation of 5-HT 2A and 5-HT 2C receptors has been suggested to induce depolarization in principal cells (Piguet and Galvan, 1994;Barnes and Sharp, 1999), but these effects appear to be dominated by the depolarizing effects of 5-HT, as bath application of 5-HT will hyperpolarize principal cells in slice preparations of the dentate gyrus (Piguet and Galvan, 1994). In addition, through 5-HT 2C , 5-HT 4 , and 5-HT 7 receptors, afterhyperpolarizing (AHP) currents are downregulated, leading to reduced adaptation in principal cells (Torres et al, 1996;Bac...

Neuropsychological study of underweight and “weight‐recovered” anorexia nervosa compared with bulimia nervosa and normal controls

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Serotonergic modulation of response inhibition and re‐engagement? Results of a study in healthy human volunteers

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The Effect of Acute Tryptophan Depletion on the Neural Correlates of Emotional Processing in Healthy Volunteers

“…Methods were not available that would allow non-invasive assessment of central 5-HT transmission or determination of the specific neurochemical mechanisms underlying the increased neurophysiological responsiveness to emotional stimuli observed during tryptophan depletion in these regions. However, it has been argued (Meeter et al, 2006) that the net effect of tonic 5-HT transmission is to hyperpolarize glutamatergic neurons (at least in the hippocampus), primarily via the 5-HT 1A receptor, but also via 5-HT 3 and 5-HT 6 receptors. It is therefore conceivable that the cause of increased responsiveness of these subcortical structures to emotional stimuli following 5-HT depletion was a loss of inhibitory tone provided by these 5-HT receptor subtypes.…”