Serotonin modulation of cortical neurons and networks

Abstract

The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

“…Moreover, some 5-HT neurons in the rat and mouse lateral wings are GABA/GAD + (70,117,(128)(129)(130)(131), and thus probably corelease GABA and 5-HT. More recent studies report that of the ascending 5-HT neurons (132)(133)(134), 16% are GABAergic and project to the medial prefrontal cortex (135), as also suggested by electrophysiological studies (136). These GAD + 5-HT neurons have distinct electrophysiological characteristics and may, interestingly, be involved in stress-related responses and disorders (130,(137)(138)(139).…”

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

“…Activation of 5-HT 2A receptors exerts complex effects upon the activity of the PFC network (18). The most prominent one is an increase in pyramidal neuron excitability, which likely results from the inhibition of slow calcium-activated after hyperpolarization current (19).…”

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“…At early stages of growth, when the blood-brain barrier is not yet completely formed, the serotonin be able to enter the brain of a developing fetus, and cause a loss of serotonin terminals through negative response. This loss of serotonin innervations persists throughout subsequent development and the symptoms of autism appear 35,44 . Thus, accumulating facts indicates that serotonergic projections undergo continuous age-related change through early childhood.…”

“…Serotonin is the neurotransmitter involved in modulating adult cortical plasticity and known to have a critical role in early cortex development by regulating proliferation, migration and neuronal differentiation 38,43 . Serotonin acts via seven families of receptors (5-HT1 -5-HT7) and is related to memory, mood, endocrine functions, sleep, learning, and muscle contraction homeostasis [44][45][46] .…”