Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study

Helboe, Lone; Egebjerg, Jan; Jong, Inge E.M. de

doi:10.1016/j.neuroscience.2015.09.064

Cited by 57 publications

(34 citation statements)

References 77 publications

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“…5-HT2 and 5-HT6 mRNA were not enriched in either ChI population by TRAP analysis. This is in line with a recent study in rats showing that 5-HT6 mRNA is highly expressed in striatal SPNs but not in ChIs (35), and suggests that 5-HT7 may play a major role in the response to 5-HT in dSt ChIs. In contrast to 5-HT7 enrichment in dSt ChIs and 5-HT1A enrichment in vSt ChIs, 5-HT5A isoform was found in both vSt and dSt ChI populations.…”

Section: Discussionsupporting

confidence: 92%

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Virk

Sagi

Medrihan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.5-HT1A | 5-HT1B | cholinergic interneurons | ventral striatum | TRAP C holinergic interneurons (ChIs) represent only 1-2% of all striatal neurons (1). Despite their low abundance, ChIs play a major role in striatal function, by modulating both inputs to and outputs from spiny projection neurons (SPNs) (2). In the ventral striatum (vSt), ChIs are thought to play a major role in mediating reward, motivation, food intake, and hedonic behavior, whereas ChIs of the dorsal striatum (dSt) are implicated in motor behavior and action selection (3-5). Despite their functional differences, only a few morphological differences between vSt and dSt ChIs have been demonstrated, but no molecular differences between these two populations have been reported (6).Serotonin [5-Hydroxytryptamine (5-HT)] signaling in the striatum has long been implicated in modulating locomotion as well as in mood control (7-9). Striatal 5-HT levels are high, and multiple 5-HT receptors (5-HTRs) are thought to mediate the function of 5-HT in these circuits (7, 10). In dSt ChIs, several 5-HTRs (5-HT7, 5-HT6, and 5-HT2) have been reported to induce membrane depolarization (11,12), but the role of 5-HT signaling in vSt ChIs and its implication for mood regulation are poorly understood. To elucidate the role of 5-HT in vSt ChIs, we used electrophysiological recordings, optogenetics, and cell type-specific gene expression analysis. We demonstrate that 5-HT1A and 5-HT1B synergistically inhibit the function of vSt ChIs. The effect of activation of 5-HT1B, but not that of 5-HT1A, is mediated by p11. Furthermore, deletion of 5-HT1B from cholinergic neurons resulted in a loss of pleasure response (anhedonia), a core symptom of major depressive disorder. ResultsOpposite Effects of 5-HT on Cell Excitability Between vSt ChIs and dSt ChIs. To investigate the effect of 5-HT on ChIs from the vSt and dSt, we carried out electrophysiological recordings from visually identified neurons in acute brain slices. To identify ChIs, we used translating ribosome affinity purification (TRAP) mice expressing a GFP-tagged ribosomal protein, L10a, under the choline acetyltrans...

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Section: Discussionsupporting

confidence: 92%

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Virk

Sagi

Medrihan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…We focused on striatal neurons since nearly all striatal medium spiny neurons express 5-HT 6 receptors in rats (Helboe et al , 2015) although, this has not been directly measured in mouse brain, and due to the importance of 5-HT 6 receptors in drug reward and procedural learning mechanisms (Brodsky et al , 2016; Eskenazi et al , 2015b). We observed no effect of the addition of a 5-HT 6 agonist on primary cilia length, but 5-HT 6 antagonists reduce striatal primary cilia length in a time- and concentration-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

et al. 2017

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The 5-HT6 receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT6 receptor function on cellular morphology has not been examined. We confirmed that 5-HT6 receptors were localized to primary cilia in wild-type (WT) but not 5-HT6 knockout (5-HT6KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT6KO mice to study the function of these receptors. Selective 5-HT6 antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time-dependent manner without altering dendrites, but had no effect on cilia length in 5-HT6KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT6 receptors affected the fidelity of ciliary localization in both WT and 5-HT6KO neurons; overexpression lead to increasing amounts of 5-HT6 localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT6 receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT6 receptor to primary cilia. These data suggest that blocking 5-HT6 receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5-HT6 receptors to cilia are more complex than previously thought.

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“…Indeed, 5-HT 6 receptor antagonists have been shown to regulate multiple neurotransmitter systems (reviewed in: Dawson, 2011). The cellular localization of the receptor, on glutamatergic and GABAergic neurons as well as select populations of GABAergic interneurons (Helboe et al, 2015), suggests that the 5-HT 6 receptor is well-positioned to regulate the balance between excitatory and inhibitory signaling, which may have a broad impact on brain activity beyond regions where the receptor is expressed.…”

Section: Introductionmentioning

confidence: 99%

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

et al. 2017

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The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

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Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study

Cited by 57 publications

References 77 publications

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

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