Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology

Abstract

The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a "classical" neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and gamma-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system.

Keywords: GABA; Serotonin; cognition; glutamate; motor control; neuromodulation; nociception.

Fig. (1)

Serotonin system. Principal groups of serotonergic neurons in the CNS and their projection sites.

Fig. (2)

Modulation of glutamate- and GABA-mediated transmission by 5-HT in the hippocampus. In the CA1 region, pre-synaptic 5-HT_1A receptors on Schaffer collaterals reduce glutamate release to pyramidal neurons [162]. 5-HT_1B receptors, located on axon terminals from pyramidal neurons and on their recurrent collaterals, inhibit glutamate release to neighboring pyramidal neurons and to local interneurons [130, 131]. The release of GABA from CA1 inhibitory interneurons is stimulated by 5-HT₂ [101, 166] and by 5-HT₃ receptors [90, 121, 157, 163, 179] and inhibited by 5-HT_1A receptors [90, 157, 163]. 5-HT and GABA_B receptors respectively increase and decrease T-type Ca²⁺ current on interneurons from stratum lacunosum-moleculare [54]. In dentate gyrus, 5-HT₄ receptors inhibit glutamate-mediated transmission [97], whereas 5-HT₃ receptors stimulate GABA release from interneurons [121, 152]. In CA3 pyramidal neurons, 5-HT inhibits GABA_B -mediated IPSCs acting both pre- and post-synaptically [145]; 5-HT and GABA_B receptors cooperate in increasing a hyperpolarizing outward potassium (K+) current [169]. A decrease in glutamate release mediated by 5-HT₆ receptors has been measured by microdialysis in the whole dorsal hippocampus [31]. Note: this figure represents a simplified scheme and does not account for the different subtypes of hippocampal interneurons.