Serotonin excites hippocampal CA1 GABAergic interneurons at the stratum radiatum-stratum lacunosum moleculare border

Wyskiel, Daniel R.; Andrade, Rodrigo

doi:10.1002/hipo.22611

Cited by 13 publications

(7 citation statements)

References 33 publications

(45 reference statements)

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“…Giving further support to this idea, Sst interneurons in the somatosensory cortex show increased cFos levels following 5-HT 2A R activation ( Martin and Nichols, 2016 ). Previous studies have reported either 5-HT 2A R-dependent inhibition or 5-HT 2A R-dependent activation of interneurons in the prefrontal cortex (PFC) ( Abi-Saab et al, 1999 ; Ashby et al, 1990 ; Athilingam et al, 2017 ), piriform cortex ( Marek and Aghajanian, 1994 ; Sheldon and Aghajanian, 1990 ), cingulate cortex ( Zhou and Hablitz, 1999 ), cochlear nucleus ( Tang and Trussell, 2017 ), amygdala ( Sengupta et al, 2017 ), olfactory bulb ( Petzold et al, 2009 ; Hardy et al, 2005 ), visual cortex ( Michaiel et al, 2019 ; Azimi et al, 2020 ), and hippocampus ( Wyskiel and Andrade, 2016 ). However, none of these studies identified interneurons using molecular markers, so we do not exclude that different interneuron classes in other cortical areas might mediate the inhibitory downstream effects of 5-HT 2A R. For example, in the PFC a subgroup of PV interneurons has been reported to be activated by this receptor ( Athilingam et al, 2017 ; Puig et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Filippo

Rost

Stumpf

et al. 2021

eLife

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Serotonin (5-HT) is one of the major neuromodulators present in the mammalian brain and has been shown to play a role in multiple physiological processes. The mechanisms by which 5-HT modulates cortical network activity, however, are not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SOs), a synchronized cortical network activity universally present across species. SOs are observed during anesthesia and are considered to be the default cortical activity pattern. We discovered that (±)3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine, two potent 5-HT releasers, inhibit SOs within the entorhinal cortex (EC) in anesthetized mice. Combining opto- and pharmacogenetic manipulations with in vitro electrophysiological recordings, we uncovered that somatostatin-expressing (Sst) interneurons activated by the 5-HT2A receptor (5-HT2AR) play an important role in the suppression of SOs. Since 5-HT2AR signaling is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, we propose that the newly discovered link between Sst interneurons and 5-HT will contribute to our understanding of these complex topics.

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Section: Discussionmentioning

confidence: 99%

Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Filippo

Rost

Stumpf

et al. 2021

eLife

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“…Prior evidence indicates that 5-HT 2A receptor agonists induce EPSPs in the cortex, likely through their expression on excitatory pyramidal neurons ( Aghajanian and Marek, 1999 , Martín-Ruiz et al., 2001 ). In contrast, 5-HT 2A receptor stimulation results in enhanced IPSPs in the hippocampus due to the presence of 5-HT 2A receptors on GABAergic interneurons and ensuing effects on GABA release ( Piguet and Galvan, 1994 , Shen and Andrade, 1998 , Wyskiel and Andrade, 2016 ). This has been suggested to contribute to the effects of 5-HT 2A receptor agonists on activity-dependent gene expression, with a robust increase noted in IEG expression in cortical brain regions and either a decline or no change in the hippocampus ( Benekareddy et al., 2013 , González-Maeso et al., 2007 ).…”

Section: Discussionmentioning

confidence: 99%

5-HT 2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

Jaggar

Weisstaub

Gingrich

2017

Neurobiology of Stress

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Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5-HT2A−/−) and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic.

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“…In the hippocampal CA1 region, the GABAergic interneurons respond to serotonin through 5-HT 2A receptors (5-HT 2A Rs) that stimulate phospholipase Cb that hydrolyzes PtdIns4,5P 2 , resulting in closure of the hyperpolarizing M current. Serotonin also induces membrane depolarization by producing InsP 3 to increase Ca 2+ that stimulates the Ca 2+ -activated nonselective cation current, resulting in membrane excitability (Wyskiel and Andrade, 2016). Dopamine acts through both the D1 and D2 receptors to regulate the formation of cyclic AMP, which also regulates neuronal excitability.…”

Section: Tonic Excitatory Drive and Depressionmentioning

confidence: 99%

Vitamin D and Depression: Cellular and Regulatory Mechanisms

Berridge

2017

Pharmacol Rev

133

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Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular Ca within the inhibitory neurons that is driven by an increase in entry through the NMDA receptors (NMDARs) and through activation of the phosphoinositide signaling pathway that generates inositol trisphosphate (InsP) that releases Ca from the internal stores. The importance of these two pathways in driving the elevation of Ca is supported by the fact that depression can be alleviated by ketamine that inhibits the NMDARs and scopolamine that inhibits the M1 receptors that drive InsP/Ca pathway. This increase in Ca not only contributes to depression but it may also explain why individuals with depression have a strong likelihood of developing Alzheimer's disease. The enhanced levels of Ca may stimulate the formation of A to initiate the onset and progression of Alzheimer's disease. Just how vitamin D acts to reduce depression is unclear. The phenotypic stability hypothesis argues that vitamin D acts by reducing the increased neuronal levels of Ca that are driving depression. This action of vitamin D depends on its function to maintain the expression of the Ca pumps and buffers that reduce Ca levels, which may explain how it acts to reduce the onset of depression.

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Serotonin excites hippocampal CA1 GABAergic interneurons at the stratum radiatum-stratum lacunosum moleculare border

Cited by 13 publications

References 33 publications

Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

5-HT 2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

Vitamin D and Depression: Cellular and Regulatory Mechanisms

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