Colocalisation of serotonin2A receptors with the glutamate receptor subunits NR1 and GluR2 in the dentate gyrus: An ultrastructural study of a modulatory role

The serotonin2A receptor (5-HT2AR) is implicated in many neurological disorders and has a role in cognitive processes, reliant upon hippocampal glutamate receptors. Recent studies show that 5-HT2AR agonists and/or antagonists can influence cognitive function, suggesting a critical hippocampal role for these receptors, yet their cellular and subcellular distribution within this region has not been comprehensively analysed. Here, we have conducted an electron microscopic examination of 5-HT2AR distribution with the glutamate N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor subunits NR1 and GluR2 in the hippocampal dentate gyrus (DG) in order to investigate whether 5-HT2AR location is compatible with a modulatory role over NMDA and/or AMPA receptor mediated neurotransmission. Of 5-HT2AR positive profiles, 56% were dendrites and 16% were dendritic spines. Labelling was both cytoplasmic and membranous. Spinous labelling was more frequently membranous at peri- and extra-synaptic sites, though was also associated with synaptic specialisations. Profiles displaying colocalisation of immunoreactivity for 5-HT2ARs with NR1 or GluR2 were predominantly dendrites, representing 11% and 8% of 5-HT2AR positive profiles, respectively. Additionally, 12% of 5-HT2AR labelled profiles also displayed immunoreactivity for γ-aminobutyric acid (GABA). These data indicate most 5-HT2ARs are expressed on granule cell projections, with a smaller subpopulation expressed on GABAergic interneurons.