Enriched Expression of Serotonin 1B and 2A Receptor Genes in Macaque Visual Cortex and their Bidirectional Modulatory Effects on Neuronal Responses

Abstract

To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.

Psychedelics

“…Certainly these illusory effects could arise through a variety of mechanisms, because 5-HT 2A receptors are expressed in many areas of the brain responsible for cognition and sensory processing. It has not been widely appreciated, however, that mammalian primary visual cortex area V1, the largest known visual cortical area, expresses a high density of 5-HT 2A receptors (Watakabe et al, 2009;Moreau et al, 2010). Microiontophoresis of DOI into macaque V1 gave a bidirectional modulatory effect on the neuron's firing rate.…”

Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations

“…Excitatory synaptic inputs in layer V modulate ␣ oscillations (Jones et al, 2000;Sun and Dan, 2009), which suggests that 5-HT2A receptor-induced excitatory effects observed in previous animal studies in layer V are closely associated with the modulation of ␣ oscillations. Finally, assuming that the presentation of external stimuli predominantly increases the firing rate of visual neurons from their prestimulus level (Quiroga et al, 2005;Montemurro et al, 2008), the opposing effects of 5-HT2A receptors on the excitability during the absence of sensory stimuli and in response to sensory stimuli are consistent with both the suppression effects of 5-HT2A receptor activation on visual neurons with high firing rates and the facilitation effects on neurons with low firing rate (Watakabe et al, 2009).…”

“…The 5-HT2A receptors in the visual cortex are primarily expressed in layers IV-VI (Watakabe et al, 2009;Moreau et al, 2010), which are crucially implicated in the generation of ␣ rhythms (Steriade et al, 1990;Bollimunta et al, 2008Bollimunta et al, , 2011. Furthermore, activation of 5-HT2A receptors in the visual cortex alters the excitatory-inhibitory balance toward excitation of neurons in layer V (Moreau et al, 2010).…”

“…5-HT2A receptors are highly expressed in the visual cortex (Gerstl et al, 2008;Watakabe et al, 2009;Moreau et al, 2010) and alterations in their cortical density in both Parkinson's disease (Ballanger et al, 2010;Huot et al, 2010) and schizophrenia (González-Maeso et al, 2008) are associated with the appearance of visual hallucinations. Furthermore, activation of 5-HT2A receptors predominantly mediates the visual hallucinations that are induced by serotonergic hallucinogens, such as psilocybin and LSD (Nichols, 2004;, whereas the 5-HT2A receptor inverse agonist pimavanserin is effective for treatment of visual hallucinations in Parkinson's disease (Meltzer et al, 2010).…”

“…5-HT2A receptors likely mediate this psilocybin-induced decrease in N170 potentials because activation of 5-HT2A receptors predominantly mediates psilocybin-induced visual hallucinations (Vollenweider et al, 1998;. However, psilocybin also activates 5-HT1A and 2C receptors (Nichols, 2004), and 5-HT1A receptors are also expressed in the visual cortex (Dyck and Cynader, 1993;Gerstl et al, 2008;Watakabe et al, 2009). Therefore, the specific effects of 5-HT2A receptors activation on visual-evoked potentials remain unknown.…”