Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment

Geddes, Sean D.; Assadzada, Saleha; Sokolovski, Alexandra; Bergeron, Richard; Haj‐Dahmane, Samir; Béı̈que, Jean-Claude

doi:10.1016/j.neuropharm.2015.02.027

Cited by 18 publications

(17 citation statements)

References 67 publications

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“…Brainstem slices containing the DRN were prepared and recorded from as previously described (15). ChR2-mediated currents were primarily generated using a PlexBright LED module (465 nm; Plexon) delivered by a 200-μm fiber patch cable.…”

Section: Methodsmentioning

confidence: 99%

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Geddes

Assadzada

Lemelin

et al. 2016

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

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Serotonin (5-HT) neurons located in the raphe nuclei modulate a wide range of behaviors by means of an expansive innervation pattern. In turn, the raphe receives a vast array of synaptic inputs, and a remaining challenge lies in understanding how these individual inputs are organized, processed, and modulated in this nucleus to contribute ultimately to the core coding features of 5-HT neurons. The details of the long-range, top-down control exerted by the medial prefrontal cortex (mPFC) in the dorsal raphe nucleus (DRN) are of particular interest, in part, because of its purported role in stress processing and mood regulation. Here, we found that the mPFC provides a direct monosynaptic, glutamatergic drive to both DRN 5-HT and GABA neurons and that this architecture was conducive to a robust feed-forward inhibition. Remarkably, activation of cannabinoid (CB) receptors differentially modulated the mPFC inputs onto these cell types in the DRN, in effect regulating the synaptic excitatory/inhibitory balance governing the excitability of 5-HT neurons. Thus, the CB system dynamically reconfigures the processing features of the DRN, a mood-related circuit believed to provide a concerted and distributed regulation of the excitability of large ensembles of brain networks.optogenetics | synapse | glutamate receptors | anxiety | depression T he phylogenetically old neurotransmitter serotonin (5-HT) is known to regulate a remarkably wide range of brain functions and behaviors, such as mood, aggression, reward, perception, levels of arousal, and decision making (1-5). The 5-HT-containing neurons are localized in a collection of small brainstem nuclei collectively known as the raphe nuclei, with the largest being the dorsal raphe nucleus (DRN). These neurons send extensive and widespread axonal projections throughout the forebrain (6). As such, the firing of a relatively small number of 5-HT neurons is powerfully poised to regulate the excitability of large ensembles of neural networks distributed across virtually the entire brain. However, little is known about how the synaptic networks impinging onto the DRN regulate the excitability of its constituent cells to generate the core feature selectivity of 5-HT neurons and, ultimately, to regulate the dynamic output of 5-HT to the brain. A significant step forward in this direction has recently been achieved by a number of anatomical studies that provide a comprehensive list of the brain regions projecting to the DRN, as well as detailed cartography of the connectivity patterns of these inputs to local cellular elements within the DRN subnetwork (i.e., 5-HT neurons, local GABAergic neurons) (7-9). The top-down control exerted by the phylogenetically recent medial prefrontal cortex (mPFC) over the DRN is of particular importance, in part, because of the purported role of this pathway in regulating several aspects of motivation and stress processing, and in mediating antidepressant-like effects (1, 10, 11). The mechanistic details of this long-range connectivity are elusive, howe...

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Section: Methodsmentioning

confidence: 99%

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Geddes

Assadzada

Lemelin

et al. 2016

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

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“…Somatic whole-cell recordings were obtained from putative DRn 5-HT neurons with patch electrodes (3–5 mΩ) filled with a solution containing (in m m ): 120 potassium gluconate; 10 KCl; 10 Na 2 -phosphocreatine; 10 HEPES; 1 MgCl 2 ; 1 EGTA; 2 Na 2 -ATP; and 0.25 Na-GTP, pH 7.3, osmolarity 280–290 mOsmol. DRn 5-HT neurons were identified by their distinct electrical properties, which include slow firing activity induced by suprathreshold membrane depolarization, large afterhyperpolarization, and membrane hyperpolarization induced by 5-HT 1A receptor agonist as previously described (Haj-Dahmane, 2001; Geddes et al 2015). …”

Section: Methodsmentioning

confidence: 99%

“…As such, determining the mechanisms that regulate the strength and plasticity of glutamate synapses onto DRn 5-HT neurons is essential for understanding the role of the 5-HT system in controlling various behaviors and physiologic functions. Although the regulation of the strength of glutamate synapses onto DRn 5HT neurons by various neurotransmitters, including 5-HT (Geddes et al 2015), noradrenaline (Haj-Dahmane and Shen, 2014), neuropeptides, and endocannabinoids (Liu et al 2002; Haj-Dahmane and Shen, 2005, 2009), has been extensively studied, it remains unknown whether these synapses undergo activity-dependent synaptic plasticity. Here, we show that glutamate synapses onto DRn 5-HT neurons exhibit spike-timing–dependent potentiation.…”

Section: Introductionmentioning

confidence: 99%

GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing–Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus

Haj‐Dahmane

Béïque

Shen

2017

eNeuro

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The dorsal raphe nucleus (DRn) receives glutamatergic inputs from numerous brain areas that control the function of DRn serotonin (5-HT) neurons. By integrating these synaptic inputs, 5-HT neurons modulate a plethora of behaviors and physiological functions. However, it remains unknown whether the excitatory inputs onto DRn 5-HT neurons can undergo activity-dependent change of strength, as well as the mechanisms that control their plasticity. Here, we describe a novel form of spike-timing–dependent long-term potentiation (tLTP) of glutamate synapses onto rat DRn 5-HT neurons. This form of synaptic plasticity is initiated by an increase in postsynaptic intracellular calcium but is maintained by a persistent increase in the probability of glutamate release. The tLTP of glutamate synapses onto DRn 5-HT is independent of NMDA receptors but requires the activation of calcium-permeable AMPA receptors and voltage-dependent calcium channels. The presynaptic expression of the tLTP is mediated by the retrograde messenger nitric oxide (NO) and activation of cGMP/PKG pathways. Collectively, these results indicate that glutamate synapses in the DRn undergo activity-dependent synaptic plasticity gated by NO signaling and unravel a previously unsuspected role of NO in controlling synaptic function and plasticity in the DRn.

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“…Antidepressants like CIT and fluvoxamine cause sexual dysfunction in rodents (Montejo et al, 2001 ; Soga et al, 2010 ), and human (Waldinger et al, 2001 ). Recent studies have shown that chronic SSRI treatment could decrease 5-HT content and signaling in the brain (Delgado et al, 1990 ; Hervás and Artigas, 1998 ), rather than simply facilitating synaptic 5-HT availability (de Jong et al, 2006 ; Geddes et al, 2015 ). Therefore, age-related and CIT induced sexual dysfunction and cognitive loss due to the decline in 5-HT in the POA may be mediated by an up-regulation of sirt4 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Aging and chronic administration of serotonin-selective reuptake inhibitor citalopram upregulate Sirt4 gene expression in the preoptic area of male mice

2015

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Sexual dysfunction and cognitive deficits are markers of the aging process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are known as aging molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT). Whether the 5-HT system regulates SIRT in the preoptic area (POA), which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10 mg/kg for 4 weeks), a potent selective-serotonin reuptake inhibitor and aging on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 weeks old mice. Furthermore, 4 weeks of chronic CIT treatment started at 8 weeks of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05). In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

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Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment

Cited by 18 publications

References 67 publications

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing–Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus

Aging and chronic administration of serotonin-selective reuptake inhibitor citalopram upregulate Sirt4 gene expression in the preoptic area of male mice

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