Serotonin enhances excitability and gamma frequency temporal integration in mouse prefrontal fast-spiking interneurons

Athilingam, Jegath; Ben-Shalom, Roy; Keeshen, Caroline M.; Bender, Kevin J.

doi:10.7554/elife.31991

Cited by 41 publications

(51 citation statements)

References 55 publications

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“…3d-g and Additional file 1: Figure S5). Although we do not clearly understand why 5-HT 2A R signaling or expression was enhanced specifically in FS interneurons, Athilingam et al recently showed that 5-HT treatment in FS interneurons resulted in the suppression of an inward-rectifying potassium conductance, which eventually lead to increased excitability of these interneurons via 5-HT 2A Rs [45], which might explain the excitability change in FS interneurons upon chronic SSRI treatment.…”

Section: Discussionmentioning

confidence: 95%

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice

Yen

Lee

et al. 2019

Mol Brain

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Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT 2A R) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT 2A R antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs. Electronic supplementary material The online version of this article (10.1186/s13041-019-0452-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 95%

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice

Yen

Lee

et al. 2019

Mol Brain

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“…Instead, the increase in membrane resistance we observe is consistent with reports that 5-HT2A receptors can reduce resting potassium conductances. In particular, these receptors have been shown to reduce an inward-rectifying potassium conductance in cortical fast spiking interneurons, thus depolarizing the membrane potential at rest (Athilingam et al 2017). 5-HT2A receptors have also been shown to depolarize feed-forward interneurons in the auditory system by reducing a resting potassium conductance (Tang and Trussell 2017).…”

Section: Discussionmentioning

confidence: 99%

Serotonin regulates dynamics of cerebellar granule cell activity by modulating tonic inhibition

Fleming

Hull

2018

Preprint

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26Understanding how afferent information is integrated by cortical structures requires identifying the 27 factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar 28 cortex integrates diverse sensorimotor information to enable learned associations that refine the 29 dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the 30 cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test 31 how this integration can be modulated, we have used an acute brain slice preparation from young 32 adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be 33 regulated by serotonin (5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes 34Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells 35 or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic 36 inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not 37 sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition 38 onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-39 forward inhibition acts to reduce granule cell spike probability without altering spike timing. These 40 data hence provide a circuit mechanism by which 5-HT can reduce granule cell activity without 41 altering temporal representations of mossy fiber input. Such changes in network integration could 42 enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be 43 learned, or enable reversal learning for unwanted associations. 44 45 New and Noteworthy 46 5-HT regulates synaptic integration at the input stage of cerebellar processing by increasing tonic 47 inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking 48 without altering spike timing, thus suppressing cerebellar input without altering its temporal 49 representation in the granule cell layer. 50 51

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“…We first made whole-cell current-clamp recordings from fluorescent neurons. Both cortical and striatal eYFP+ cells responded to somatic current injection with high-frequency action potential firing and with sharp afterhyperpolarizations typically observed in FSIs [25,26] (Fig. 4A-B).…”

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confidence: 89%

Knock-in rats expressing Cre and Flp recombinases at the Parvalbumin locus

Pettibone

Chen

et al. 2018

Preprint

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Rats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either Cre or Flp recombinase under the control of Parvalbumin (Pvalb), a gene expressed in the critical "fast-spiking" subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of Pvalb-expressing neurons, as demonstrated by in situ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both ex vivo and in vivo approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments. IntroductionThe extensive library of recombinase driver mouse models [1,2] has enabled precise functional and structural dissection of neural circuits by providing specific and reliable genetic access to molecularly defined neural populations. When used in combination with recombinase-dependent reporter models or viruses, reporter genes can be expressed in specific neural populations [3]. For complex behavioral and large-scale in vivo electrophysiological experiments, rats are the model of choice. Yet their usefulness is restricted by the limited number of transgenic recombinase driver models to label molecularly defined neural populations. Thus, reliable rat recombinase driver models have great potential for accelerating progress in neuroscience.One important application of recombinase driver models is to suppress local brain activity in real time. This can be effectively achieved by optogenetic stimulation of local inhibitory interneurons, as demonstrated in mice using inhibitory neuron-specific Cre models [2,4]. In both cortical [5] and subcortical [6] regions, Parvalbumin (Pvalb) is expressed by GABAergic interneurons that provide perisomatic inhibition to projection neurons [7]. A rat recombinase driver model that directs transgene expression to Pvalb+ interneurons will therefore be a powerful tool for temporally-precise control of local circuit function.Until recently, it has been difficult to insert exogenous genes of interest into specific genomic locations in rats, primarily due to the lack of pluripotent stem cells for in vitro genomic modification [8]. To overcome this limitation, genetically modified rats have been predominantly generated using Bacterial Artificial Chromosome (BAC) transgenic technology [9][10][11]. This involves inserting a large chunk of chromosomal DNA (200-300kb) into the genome that includes the promoter of interest, coupled with an additional coding sequence for the desired recombinase. Expres...

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Serotonin enhances excitability and gamma frequency temporal integration in mouse prefrontal fast-spiking interneurons

Cited by 41 publications

References 55 publications

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice

Serotonin regulates dynamics of cerebellar granule cell activity by modulating tonic inhibition

Knock-in rats expressing Cre and Flp recombinases at the Parvalbumin locus

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