5-HT6 receptors: Contemporary views on their neurobiological and pharmacological relevance in neuropsychiatric disorders.

Despite the relatively limited number of serotonergic neurons in humans, serotonin plays a key role in neurophysiological functions, including sleep, pain perception, learning, memory, cognition, emotion, reward, and mood regulation. Altered serotonergic neurotransmission is linked to conditions such as anxiety, depression, anorexia, migraine, insomnia, schizophrenia, Alzheimer's disease (AD), and cognitive impairments. The 5-HT6 receptor (5-HT6R), mainly found in brain regions involved in cognition, is a promising therapeutic target for cognitive deficits in neuropsychiatric disorders, particularly AD and schizophrenia. Preclinical studies have shown that 5-HT6R antagonists improve cognitive function. 5-HT6R interacts dynamically with an extensive intracellular protein network, regulating the localisation, trafficking, and signalling of these proteins. Proteomic and genetic studies have revealed interactions with mTOR kinase and neurofibromin, both of which are crucial for synaptic plasticity, learning, and memory. Fyn kinase is also associated with 5-HT6Rs, reinforcing receptor expression and G-protein coupling. Notably, the G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) interacts with 5-HT6Rs independently of agonists, enhancing receptor activity. This review highlights the clinical testing of 5-HT6R ligands as regulators of these complex signalling properties, underscoring their therapeutic potential in addressing cognitive impairments associated with neuropsychiatric disorders.