Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders

Abstract

The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.

Serotonin in Animal Cognition and Behavior

“…The stimulation of 5-HT 4 R may also inhibit feeding behavior in rodents, likely via its action at the level of the nucleus accumbens [134,135]. Its higher expression in the nucleus accumbens and ventral pallidum has been associated with a higher body mass index in humans [136,137].…”

“…The precise influence of 5-HTR subtypes deserves additional studies in view of their possible targeting in the clinic as cognitive enhancer [184]. It has been recently stressed out for 5-HT 4 R and 5-HT 6 R subtypes [137,185]. Several 5-HT 6 R antagonists have been tested in recent clinical trials in Alzheimer patients although the results were mitigated [186].…”

Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities

“…Defective sorting of AMPA receptors have been previously proposed to mediate at least some of these effects . Other neuroactive proteins probably influenced by SNX27 include several neuroreceptors (5‐HT 4 , AMPA, NMDA and mGluR5), ATPase copper transporting alpha (ATP7a, Menkes disease) and glucose transporter 1 (GLUT1, infantile epilepsy), disintegrin and metalloproteinase domain‐containing protein 22 (ADAM22; encephalopathy, cortical atrophy and epilepsy), and neuroligin 2 (NLGN2; autism, intellectual disability, anxiety). GLUT1 and ATP7A are unlikely to be major or clinically significant mediators in view of normal glucose levels in blood and cerebrospinal fluid glucose in the previously described family and normal cerelluplasmin and copper levels, as well as hair, in Patient 1 in this report.…”

“…Relevant known interaction partners, and their known (solid lines) or proposed (dashed lines) downstream interaction partners, physiologic consequences or phenotypic outcomes are shown. Interaction partners include several neuroreceptors (5‐HT 4, AMPA, NMDA and mGluR5), ATP7a, GLUT1, ADAM22, NLGN2, MCTP2, and CFTR . Possible downstream mediators include MAM domain‐containing glycosylphosphatidylinositol anchor protein 1 (MDGA1) or Notch .…”

Molecular Psychiatry: Trends and Study Examples

“…Finally, in light of evidence suggesting an important role for the serotonergic system in many physiological and pathological conditions, including psychiatric disorders, the paper by Rebholz and colleagues reviewed biological findings regarding the serotonin 4 receptor (5-HT4R) [20] in brain regions and how its genetic regulation and gene expression changes can modulate reward and executive function and potentially give rise to mood changes in vulnerable subjects. The authors also extend their discussion to explore methodological advancements that will be needed for a better understanding of this receptor in brain function, including the development of more suitable genetic mouse models.…”