Effects of serotonin on the intrinsic membrane properties of layer II medial entorhinal cortex neurons

Ma, Li; Shalinsky, Mark H.; Alonso, Ángel; Dickson, Clayton T.

doi:10.1002/hipo.20250

Cited by 21 publications

(20 citation statements)

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“…Whereas it is generally recognized that 5-HT reduces neuronal excitability in the superficial layers of the EC via activation of K ϩ channels (Grü nschlag et al, 1997;Ma et al, 2006), the characteristics of the K ϩ channels have not been determined. Our results demonstrate that 5-HT-induced increase in outward holding current was insensitive to the classic K ϩ channel blockers (TEA, 4-AP, Cs ϩ ) but sensitive to Ba 2ϩ and bupivacaine.…”

Section: Discussionmentioning

confidence: 99%

“…The raphe nuclei send strong serotonergic projections to the superficial layers of the EC (Bobillier et al, 1975), where high densities of serotonin [5-hydroxytryptamine (5-HT)] receptors are expressed (Pazos and Palacios, 1985). Although the exact actions of 5-HT in the EC remain to be explored, application of 5-HT to this region generally inhibits synaptic transmission (Schmitz et al, 1998) and neuronal excitability, possibly via activating K ϩ channels (Grü nschlag et al, 1997;Ma et al, 2006). However, the ionic and signaling mechanisms underlying 5-HT-mediated inhibition in the EC have not been elucidated.…”

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confidence: 99%

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Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex

Deng

Poudel²,

Rojanathammanee³

et al. 2007

Mol Pharmacol

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The entorhinal cortex (EC) is regarded as the gateway to the hippocampus; the superficial layers (layers I-III) of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. The superficial layers of the EC receive strong serotonergic projections from the raphe nuclei. However, the function of serotonin in the EC is still elusive. In the present study, we examined the molecular and cellular mechanisms underlying serotonin-mediated inhibition of the neuronal excitability in the superficial layers (layers II and III) of the EC. Application of serotonin inhibited the excitability of stellate and pyramidal neurons in the superficial layers of the EC by activating the TWIK-1 type of the two-pore domain K ϩ channels. The effects of 5-HT were mediated via 5-HT 1A receptors and required the function of G␣ i3 subunit and protein kinase A. Serotonin-mediated inhibition of EC activity resulted in an inhibition of hippocampal function. Our study provides a cellular mechanism that might at least partially explain the roles of serotonin in many physiological functions and neurological diseases.The entorhinal cortex (EC) is regarded as the gateway to the hippocampus because it mediates the majority of connections between the hippocampus and other cortical areas. Sensory inputs converge onto the superficial layers (layers I-III) of the EC, which give rise to dense projections to the hippocampus; the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus and commissura anterior 3, whereas the pyramidal neurons in layer II/III provide the primary input to commissura anterior 1 regions (Steward and Scoville, 1976;Witter et al., 1989). On the other hand, neurons in the deep layers of the EC (layers IV-VI) relay a large portion of hippocampal output projections back to the superficial layers of the EC (van Haeften et al., 2003) and to other cortical areas (Witter et al., 1989). The EC is part of a network that aids in the consolidation and recall of memories (for review, see Steffenach et al., 2005). Neuronal pathology and atrophy of the EC are potential contributors to Alzheimer's disease (Kotzbauer et al., 2001) and schizophrenia (Prasad et al., 2004). Furthermore, the EC plays an important role in the induction and maintenance of temporal lobe epilepsy (Spencer and Spencer, 1994).The EC receives information from both the cortical mantle and the brain stem. The raphe nuclei send strong serotonergic projections to the superficial layers of the EC (Bobillier et al., 1975), where high densities of serotonin [5-hydroxytryptamine (5-HT)] receptors are expressed (Pazos and Palacios, 1985). Although the exact actions of 5-HT in the EC remain to be explored, application of 5-HT to this region generally This work was supported by National Institutes of Health grant 5P20-RR017699-02 from the Centers of Biomedical Research Excellence prog...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex

Deng

Poudel²,

Rojanathammanee³

et al. 2007

Mol Pharmacol

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“…The physiological actions of these receptors on pyramidal neurons have been characterized in in vitro electrophysiological studies (Andrade et al, 1986; Araneda and Andrade, 1991; Béïque et al, 2004; Villalobos et al, 2005; Zhang and Arsenault, 2005; Ma et al, 2007). In interneurons, 5-HT 2A receptors have been described in in vitro studies to increase neuronal excitability (Deng et al, 2007; Puig et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Serotonergic modulation of spatial working memory: predictions from a computational network model

Cano-Colino¹,

Almeida²,

Compte³

2013

Front. Integr. Neurosci.

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Serotonin (5-HT) receptors of types 1A and 2A are strongly expressed in prefrontal cortex (PFC) neurons, an area associated with cognitive function. Hence, 5-HT could be effective in modulating prefrontal-dependent cognitive functions, such as spatial working memory (SWM). However, a direct association between 5-HT and SWM has proved elusive in psycho-pharmacological studies. Recently, a computational network model of the PFC microcircuit was used to explore the relationship between 5-HT and SWM (Cano-Colino et al., 2013). This study found that both excessive and insufficient 5-HT levels lead to impaired SWM performance in the network, and it concluded that analyzing behavioral responses based on confidence reports could facilitate the experimental identification of SWM behavioral effects of 5-HT neuromodulation. Such analyses may have confounds based on our limited understanding of metacognitive processes. Here, we extend these results by deriving three additional predictions from the model that do not rely on confidence reports. Firstly, only excessive levels of 5-HT should result in SWM deficits that increase with delay duration. Secondly, excessive 5-HT baseline concentration makes the network vulnerable to distractors at distances that were robust to distraction in control conditions, while the network still ignores distractors efficiently for low 5-HT levels that impair SWM. Finally, 5-HT modulates neuronal memory fields in neurophysiological experiments: Neurons should be better tuned to the cued stimulus than to the behavioral report for excessive 5-HT levels, while the reverse should happen for low 5-HT concentrations. In all our simulations agonists of 5-HT1A receptors and antagonists of 5-HT2A receptors produced behavioral and physiological effects in line with global 5-HT level increases. Our model makes specific predictions to be tested experimentally and advance our understanding of the neural basis of SWM and its neuromodulation by 5-HT receptors.

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“…In the lateral entorhinal cortex, 5-HT reduces input resistance and hyperpolarizes layer II/III neurons through potassium channels coupled to 5-HT 1A receptors (Grünschlag et al 1997). In the medial entorhinal cortex, 5-HT evokes a biphasic response, first hyperpolarizing neurons via 5-HT 1A receptors and then depolarizing neurons by an I h channel-dependent mechanism (Ma et al 2007). The role of 5-HT in regulating cortical excitability therefore depends on the developmental trajectory and activitydependent expression of both specific receptor subtypes and target ion channels.…”

Section: Introductionmentioning

confidence: 98%

Hearing Loss Alters Serotonergic Modulation of Intrinsic Excitability in Auditory Cortex

Rao

Basura²,

Roche³

et al. 2010

Journal of Neurophysiology

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Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 μM) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that early sensorineural hearing loss affects the ability of 5-HT receptor activation to modulate A1 pyramidal cell excitability.

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Effects of serotonin on the intrinsic membrane properties of layer II medial entorhinal cortex neurons

Cited by 21 publications

References 80 publications

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex

Serotonergic modulation of spatial working memory: predictions from a computational network model

Hearing Loss Alters Serotonergic Modulation of Intrinsic Excitability in Auditory Cortex

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Effects of serotonin on the intrinsic membrane properties of layer II medial entorhinal cortex neurons

Cited by 21 publications

References 80 publications

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K+ Channels in the Entorhinal Cortex

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K+ Channels in the Entorhinal Cortex

Serotonergic modulation of spatial working memory: predictions from a computational network model

Hearing Loss Alters Serotonergic Modulation of Intrinsic Excitability in Auditory Cortex

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Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex

Serotonin Inhibits Neuronal Excitability by Activating Two-Pore Domain K⁺ Channels in the Entorhinal Cortex