5‐Hydroxytryptamine1A receptor‐activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

• Published in: The Journal of physiology Vol. 592; no. 19; pp. 4187 - 4199
• Main Authors: Johnston, April, McBain, Chris J., Fisahn, André
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2014; Blackwell Science Inc
• Subjects: Animals; Excitatory Amino Acid Agonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Hippocampus - drug effects; Hippocampus - physiology; Kainic Acid - pharmacology; Medicin och hälsovetenskap; Neuroscience: Cellular/Molecular; Patch-Clamp Techniques; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin - pharmacology; Serotonin 5-HT1 Receptor Agonists - pharmacology
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/jphysiol.2014.279083

Key points Rhythmic activity in the gamma frequency range (30–80 Hz) in the hippocampus is modulated by neurotransmitters such as serotonin, dopamine and histamine. Multiple different serotonin receptors are expressed in the hippocampus. Here we show that serotonin suppresses hippocampal gamma oscillations via activation of the receptor 5‐HT1A. The cellular cause for suppressed gamma oscillations is the 5‐HT1A receptor‐induced hyperpolarization and afterpolarization frequency reduction of pyramidal cells, but not of parvalbumin‐positive interneurons. The pyramidal cell hyperpolarization is mediated by an inwardly rectifying current mediated by the Kir3 potassium channel known to couple to 5‐HT1A, which also results in decreased firing frequency. Rhythmic cortical neuronal oscillations in the gamma frequency band (30–80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease. In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin (5‐HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5‐HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5‐HT reduce the power of induced gamma oscillations. Hypothesizing that 5‐HT may have cell‐ and receptor subtype‐specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5‐HT in the modulation of gamma oscillations in mice and rats. We found that 5‐HT decreases the power of kainate‐induced hippocampal gamma oscillations in both species via the 5‐HT1A receptor subtype. Whole‐cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein‐coupled receptor inwardly rectifying potassium channel Kir3. Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re‐establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders.