Serotonin Receptors and Central Nervous System Functions

Serotonin, or 5-hydroxytryptamine (5-HT), is a ubiquitous neurotransmitter that exerts wide-ranging effects on the central nervous system (CNS) through activation of at least fourteen receptor subtypes. These receptors, classified into seven families (5-HT1 to 5-HT7), include G-protein coupled receptors (GPCRs) and a ligand-gated ion channel (5-HT3). Expressed throughout cortical, limbic and brainstem regions, 5-HT receptors regulate mood, cognition, motor function, sleep and autonomic processes. Fine-tuning of synaptic transmission and neuroplasticity is achieved via receptor-specific coupling to intracellular cascades—cAMP modulation, ion flux and kinase activation. Dysregulation of serotonergic signalling underlies depression, anxiety, schizophrenia and neurodevelopmental disorders, rendering these receptors pivotal therapeutic targets. Advances in receptor-selective ligands and receptor–receptor interactions have deepened understanding of synaptic maturation, emotional learning and neuroprotection, with implications for novel treatments across psychiatric and neurological domains.

Research from Nature Portfolio

Recent studies have delineated a synaptic mechanism by which 5-HT modulates excitatory spine maturation in the prefrontal cortex during early postnatal development. Chemogenetic manipulation of 5-HT release in mice revealed that both suppression and enhancement of serotonergic signalling bidirectionally regulate spine density and strength on layer 2/3 pyramidal neurons. Spine-specific 5-HT stimuli induced long-term potentiation independently of glutamatergic activity, requiring co-activation of 5-HT2A and 5-HT7 receptors and engaging Gαs-dependent pathways to stabilise newly formed spines. Chronic administration of a selective serotonin reuptake inhibitor within a critical developmental window produced analogous synaptic enhancements, an effect abolished by 5-HT2A and 5-HT7 antagonists. These findings uncover a molecular framework for 5-HT-dependent plasticity and suggest precise receptor targets for developmental interventions.

Serotonin Receptors and Central Nervous System Functions publication trend

The graph below shows the total number of articles in serotonin receptors and central nervous system functions across all publications each year (not limited to Nature Index journals).

Technical terms

Serotonin (5-HT): Neurotransmitter that modulates mood, cognition and various physiological processes in the CNS.

G-protein coupled receptor (GPCR): Seven-transmembrane protein that transduces extracellular signals via G-protein activation.

Synaptic plasticity: Activity-dependent changes in synaptic strength underlying learning and memory.

Long-term potentiation (LTP): Persistent increase in synaptic efficacy following high-frequency stimulation.

Agonist: Molecule that binds to a receptor and elicits a physiological response.

Antagonist: Molecule that binds to a receptor and inhibits its activation.

Dimerisation: Formation of receptor homo- or heterodimers affecting signalling and trafficking.

Gut–brain axis: Bidirectional communication network between the gastrointestinal tract and the CNS.

References

1. Lepidium meyenii Walp (Maca)‐derived extracellular vesicles ameliorate depression by promoting 5‐HT synthesis via the modulation of gut–brain axis. iMeta (2023).
2. Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Nature Communications (2024).
3. The 5-HT7 receptor system as a treatment target for mood and anxiety disorders: A systematic review. Journal of Psychopharmacology (2023).
4. Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders. International Journal of Molecular Sciences (2023).