5‐Hydroxytryptamine_1A receptor‐activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

Abstract

Key pointsr Rhythmic activity in the gamma frequency range in the hippocampus is modulated by neurotransmitters such as serotonin, dopamine and histamine.r Multiple different serotonin receptors are expressed in the hippocampus. r Here we show that serotonin suppresses hippocampal gamma oscillations via activation of the receptor 5-HT 1A .r The cellular cause for suppressed gamma oscillations is the 5-HT 1A receptor-induced hyperpolarization and afterpolarization frequency reduction of pyramidal cells, but not of parvalbumin-positive interneurons.r The pyramidal cell hyperpolarization is mediated by an inwardly rectifying current mediated by the Kir3 potassium channel known to couple to 5-HT 1A , which also results in decreased firing frequency.Abstract 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-HT 1A 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.

Serotonin differentially modulates excitatory and inhibitory synaptic inputs to putative sleep-promoting neurons of the ventrolateral preoptic nucleus

“…Our results indicate that Type-1 and Type-2 Gal-GFP neurons and nonfluorescent neurons within the VLPO express 3 different sets of mRNAs. Type-1 neurons express mRNAs that encode 5-HT 1A receptors in particular; these receptors likely mediate the hyperpolarizing effect of 5-HT, similar to what has been reported for many other brain regions (Cheng et al, 1998;Haj os et al, 2003;Johnston et al, 2014). In addition, these neurons express mRNAs for the 5-HT 1B,D,F and 5-HT 5A receptors, which could participate in the inhibitory response toward 5-HT application, since these receptors are negatively coupled to cAMP levels via the Gi/Go protein (Francken et al, 1998;Lin et al, 2002).…”

Serotonergic Suppression of Mouse Prefrontal Circuits Implicated in Task Attention

“…These two receptors show substantial colocalization in L6 pyramidal neurons in mPFC of mouse (Table 3 in Amargós-Bosch et al, 2004), yet typically appear to exert opposing electrophysiological effects in other cortical layers (Benekareddy et al, 2010; Avesar and Gulledge, 2012; Stephens et al, 2014). Whereas 5-HT 1A receptors are known inhibitory receptors acting via Kir3 channels (Goodfellow et al, 2014; Johnston et al, 2014), 5-HT 2A receptors act through a less well-characterized set of channels to excite certain populations of neurons, including a subset of L5 pyramidal neurons in mPFC (Willins et al, 1999; Benekareddy et al, 2010; Weber and Andrade, 2010; Avesar and Gulledge, 2012). Direct inhibition of L6 pyramidal neurons by 5-HT 2A receptors could arise from a number of possible mechanisms, including the suppression of sodium channels (Carr et al, 2002) or via 5-HT 2A heteromers with inhibitory signaling (González-Maeso et al, 2007; Moreno et al, 2011; Viñals et al, 2015).…”

Serotonin dependent masking of hippocampal sharp wave ripples

“…7B, n ¼ 8). 8-0H-DPAT is known to hyperpolarize pyramidal cells and certain interneurons (Andrade and Nicoll, 1987;Schmitz et al, 1995b;Johnston et al, 2014). The 5-HT 2A/C agonist alpha-methylserotonin (aMe 5-HT 20 mM) was also capable of suppressing SPW-Rs (Fig.…”