Transient Expression of Serotonin 5-HT4 Receptors in the Developing Thalamocortical Projections

Background: The 5-HT₄ receptor is an unusually complex serotonin receptor that may underlie the co-morbidity of central and peripheral abnormalities in autism spectrum disorders (ASDs). 5-HT₄ receptors are expressed in the developing brain, the gastrointestinal (GI) system, and blood platelets. Mice lacking the 5-HT_1A receptor, another serotonin receptor expressed in the brain and the GI system, show both elevated levels of anxiety (Gross et al., 2002) and elevated serotonin levels in blood platelets (Janušonis et al., 2006). Likewise, abnormal function of 5-HT₄ receptors may potentially alter brain development and lead to GI and blood serotonin pathologies.

Objectives: As part of our system-level approach (Janušonis, 2008; Albay et al., 2009), in the present study we investigated the expression of 5-HT₄ receptors in the developing embryonic forebrain in mice.

Methods: We studied the expression of 5-HT₄ receptors in the mouse forebrain at embryonic days 13, 15, 17, and at postnatal days 3 and 14 by using immunohistochemistry, immunoelectron microscopy, tract tracing, and quantitative RT-PCR.

Results: The embryonic thalamocortical projections transiently expressed 5-HT₄ receptors, suggesting that 5-HT₄ receptors may be important for the normal development of these major sensory and limbic projections. Also, the 5-HT₄ receptor expression in the forebrain changed from axonal to somatic around birth. From embryonic day 13 to 17, the telencephalic mRNA levels of the 5-HT_4(a) and 5-HT_4(b) splice variants increased nine- and five-fold, respectively, whereas the levels of the 5-HT_4(e) and 5-HT_4(f) variants remained low and statistically unchanged throughout the studied period of embryonic development.

Conclusions: These results show that during development the 5-HT₄ receptor expression in the forebrain undergoes a dynamic regulation. Since the serotonin system is highly conserved in mammalian species, our findings also suggest that perturbation of this regulation may be a contributing factor in ASDs. We are currently investigating whether 5-HT₄ receptors exhibit the same expression dynamics in the developing human brain.