Role of the 5-HT7 Receptor in the Central Nervous System: from Current Status to Future Perspectives

Abstract

Pharmacological and genetic tools targeting the 5-hydroxytryptamine (5-HT)7 receptor in preclinical animal models have implicated this receptor in diverse (patho)physiological processes of the central nervous system (CNS). Some data obtained with 5-HT7 receptor knockout mice, selective antagonists, and, to a lesser extent, agonists, however, are quite contradictory. In this review, we not only discuss in detail the role of the 5-HT7 receptor in the CNS but also propose some hypothetical models, which could explain the observed inconsistencies. These models are based on two novel concepts within the field of G protein-coupled receptors (GPCR), namely biphasic signaling and G protein-independent signaling, which both have been shown to be mediated by GPCR dimerization. This led us to suggest that the 5-HT7 receptor could reside in different dimeric contexts and initiate different signaling pathways, depending on the neuronal circuitry and/or brain region. In conclusion, we highlight GPCR dimerization and G protein-independent signaling as two promising future directions in 5-HT7 receptor research, which ultimately might lead to the development of more efficient dimer- and/or pathway-specific therapeutics.

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

“…The involvement of 5-HT7R in fear conditioning has been demonstrated in 5-HT7R KO mice, which displayed impaired contextual fear conditioning along with decreased longterm synaptic plasticity within the CA1 region of the hippocampus (Roberts et al, 2004). Based on preclinical findings, 5-HT7Rs are now emerging as a possible therapeutic target for the treatment of cognitive disorders and depression (Gasbarri et al, 2008, Matthys et al, 2011and Volpicelli et al, 2014. For example, treatment with selective 5-HT7R antagonists has been shown to have anxiolitic and antidepressant effects in mice tested in the forced swim and tail suspension tests (Nikiforuk, 2015).…”

“…Among the 5-HT receptor subtypes potentially involved in activity-induced plasticity, the 5-HT7 receptor (5-HT7R) has recently received much attention because of its broad expression in central nervous system, specially in thalamus, hypothalamus, hippocampus, striatum and cortex (Matthys et al, 2011). Contextual learning, spatial memory and hippocampal long-term synaptic plasticity are all impaired in mice treated with selective antagonists of 5-HT7R as well as in 5-HT7R knockout (KO) mice (Roberts et al, 2004;Roberts and Hedlund, 2012).…”

Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder

“…Since its identification the 5-HT 7 receptor has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain and by the discovery that several nonselective antipsychotics and antidepressants currently on the market display high affinity for this receptor (Stahl, 2010;Leopoldo et al, 2011;Matthys et al, 2011). The 5-HT 7 receptor is positively coupled to adenylate cyclase with a pharmacological profile distinct from all other 5-HT receptor subtypes.…”

Lifting the Mood on Treating Fragile X

“…Multiple behavioral studies have shown that antagonism of 5-HT 7 receptors impairs long-term memory, and studies using 5-HT 7 agonists show a beneficial effect on instrumental and associative memory formation (reviewed in Roberts and Hedlund [8]). Consistent with these findings, studies performed on 5-HT 7 knockout mice show a deficit in contextual fear conditioning, a hippocampal learning task, as well as deficient LTP in hippocampal CA1 (9). However, the mechanism through which 5-HT 7 activation enhances memory formation is largely unknown.…”