Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex

Abstract

Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin -2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.

Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

“…Our unpublished data corroborates a recent publication 36 which demonstrated that the majority of GABA neurons in the prelimbic mPFC expressed 5-HT 2C R immunoreactivity and most co-expressed 5-HT 2A R immunoreactivity; a small population of cells with a pyramidal profile also expressed both receptors. The colocalization of the receptors in the same neuron suggests that the 5-HT 2A R:5-HT 2C R protein complex may occur at the single cell level.…”

“…36 Given the association of 5-HT 2A R and 5-HT 2C R proteins in mPFC with levels of motor impulsivity (Fig. 2), 6,9 we further considered the possibility that a 5-HT 2A R:5-HT 2C R protein complex may exist in the mPFC and that the pattern of complex formation may track with inherent motor impulsivity.…”

“…10,28–31 The mRNA and/or protein for both the 5-HT 2A R and 5-HT 2C R are found in glutamatergic and GABAergic neurons in the mPFC. 32–36 Localized infusion of DOI into the mPFC enhances 37 while intra-mPFC M100907 38 suppresses premature responding assessed in the 5-CSRT task. The density of 5-HT 2A R 9 as well as 5-HT 2C R 6 protein expression in the mPFC predicts premature responses in the 1-CSRT task in outbred rats.…”

Neural connection supporting endogenous 5-hydroxytryptamine influence on autonomic activity in medial prefrontal cortex

“…Diverse subtypes of 5-HT receptors have been localized to mPFC pyramidal neurons, including 5-HT 1 (1A, 1B and 1D), 5-HT 2 (2A and 2C), 5-HT 4 , 5-HT 6 and/or 5-HT 7 (Bard et al, 1993;Feng et al, 2001;Miner et al, 2003;Celada et al, 2013;Shoemaker et al, 2015), and coexpression of these receptors with different combinations is detected on the majority of mPFC neurons (Feng et al, 2001;Puig and Gulledge, 2011;Nocjar et al, 2015).…”

“…Different 5-HT receptor subtypes can interact, resulting in complex effects. For instance, the 5-HT 2C RNA editing isoforms, displaying differential constitutive activities, differentially affect the dynamic change of conformation, sensitivity and receptor trafficking of both 5-HT 2A and5-HT 2c receptors, if they are colocalized (Berg et al, 2005;Nocjar et al, 2015). In addition, one 5-HT receptor may mediate different responses, which can be exemplified by the resulting inhibition following 5-HT 2A exposure to milieu 5-HT of a concentration over 50 nM (Arvanov et al, 1999), an effect opposite to the frequently observed excitation.…”