Project Summary
Although functional gastrointestinal (GI) disorders (FGIDs) are the most common causes of bowel
dysfunction worldwide, many patients are inadequately treated because current therapies are frequently
ineffective. The inadequacy of therapy is largely due to an incomplete comprehension of underlying
mechanisms that are critical for the design of new treatments. Up to half of individuals with FGIDs also suffer
from mood disorders. Evidence supports the idea that the GI tract is vulnerable to genetic perturbations that
can exert lasting effects on GI function and mood. It is thus conceivable that a co-morbid FGID and psychiatric
condition result from abnormalities occurring as the result of a genetic variant. Discovery of the
pathophysiology underlying FGIDs and psychiatric co-morbidities is likely to enhance understanding of their
relationship and thus lead to novel therapies for both. Serotonin (5-HT), which is a major determinant of enteric
and central nervous system (ENS and CNS) development and also modulates FGID-related symptoms (GI
motility) as well as mood, may be an important developmental modulator of FGID pathogenesis. It is 5-HT
stimulation of the 5-HT4 receptor, however, that has the most well-studied prokinetic, anti-nociceptive, anti-
depressive, and anti-anxiety effects and has thus been targeted to treat both GI dysmotility and mood
dysfunction. Curiously, however, >50% of patients with FGIDs are relatively unresponsive to them. The
reason for 5-HT4 treatment failure is unknown, making this a critical treatment obstacle. Our preliminary data
strongly suggest that failure to respond to a 5-HT4 agonist is due to a defect in 5-HT4 trafficking. Although
defects in enteric 5-HT4 trafficking have never previously been explored, such abnormalities have been
described in the CNS; p11 is a critical adaptor molecule involved in this transport of 5-HT4 receptors to cell
surfaces, where the receptors become available to mediate 5-HT signaling. P11 also plays a role in depression
(p11KO mice exhibit depressive behaviors and CNS p11 transcription is impaired in mouse models of
depression and human suicide victims). We have found that in the ENS, as in the CNS, gut p11 is co-
expressed with 5-HT4 receptors where they co-immunoprecipitate, suggesting that p11 interacts with 5-HT4 in
the gut and, further, that p11 affects 5-HT4 receptor-mediated actions on ENS development and GI motility. Our
hypotheses are thus that p11 facilitation of trafficking of 5-HT4 receptors to cell surfaces is essential for 5-HT4-
modulation of ENS development and function and that p11 dysfunction thus underlies comorbid FGID and
depression. In this application we will explore: (1) How critical the p11-5-HT4 interaction is for effective GI
motility utilizing a comprehensive array of in vivo and ex vivo studies ± the selective 5-HT4 agonist,
prucalopride, in WT and p11KO mice; (2) If effects of p11 on mood (depression / anxiety), ENS development,
and GI motility depend on mucosal or enteric neuronal p11, using novel transgenic mice that selectively lack
p11 in the enteric epithelium or ENS and; (3) If enteric 5-HT4 trafficking and function are p11-dependent.
