Nicotinic Acetylcholine Receptor β2 Subunits in the Medial Prefrontal Cortex Control Attention

Guillem, Karine; Bloem, Bernard; Poorthuis, Rogier B.; Loos, Maarten; Smit, August B.; Maskos, Uwe; Spijker, Sabine; Mansvelder, Huibert D.

doi:10.1126/science.1207079

Cited by 183 publications

(162 citation statements)

References 28 publications

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“…It has been reported that the β2 subunit is involved in the dendritic morphogenesis of pyramidal neurons, and in particular, in the circuits that contribute to the high-order functional connectivity of the cerebral cortex (40). These defects in the maturation of the cerebral cortex that have been reported in the β2 KO mice could contribute to the observed behavioral deficits (4,13,16). However, our data reveal that pharmacological intervention with nicotinic antagonists is enough for the disruption of USF mechanisms.…”

Section: Discussioncontrasting

confidence: 53%

“…Importantly, lesions of the prelimbic cortex (PrLC) in WT mice cause deficits in social behavior, similar to those observed in β2 knock-out (KO) mice, whereas re-expression of the β2 subunit in the PrLC of β2 KO mice rescues their social interaction (4). Similarly, re-expression of β2 subunits in the PrLC of β2 KO mice fully restored their attentional performance in the five-choice serial reaction time task (16).…”

mentioning

confidence: 94%

“…Many studies in both animal models and humans have shown that nicotinic acetylcholine receptors (nAChRs) are of particular importance for cognitive functions, reward, aging, and for pathologies like Alzheimer's Disease (11). For example, deletion of the α7 and β2 nAChR subunits in mice impairs behaviors, such as exploration and attention (12)(13)(14)(15)(16). Importantly, lesions of the prelimbic cortex (PrLC) in WT mice cause deficits in social behavior, similar to those observed in β2 knock-out (KO) mice, whereas re-expression of the β2 subunit in the PrLC of β2 KO mice rescues their social interaction (4).…”

mentioning

confidence: 99%

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Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

Koukouli

Rooy

Changeux

et al. 2016

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

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The prefrontal cortex (PFC) plays an important role in cognitive processes, including access to consciousness. The PFC receives significant cholinergic innervation and nicotinic acetylcholine receptors (nAChRs) contribute greatly to the effects of acetylcholine signaling. Using in vivo two-photon imaging of both awake and anesthetized mice, we recorded spontaneous, ongoing neuronal activity in layer II/III in the PFC of WT mice and mice deleted for different nAChR subunits. As in humans, this activity is characterized by synchronous ultraslow fluctuations and neuronal synchronicity is disrupted by light general anesthesia. Both the α7 and β2 nAChR subunits play an important role in the generation of ultraslow fluctuations that occur to a different extent during quiet wakefulness and light general anesthesia. The β2 subunit is specifically required for synchronized activity patterns. Furthermore, chronic application of mecamylamine, an antagonist of nAChRs, disrupts the generation of ultraslow fluctuations. Our findings provide new insight into the ongoing spontaneous activity in the awake and anesthetized state, and the role of cholinergic neurotransmission in the orchestration of cognitive functions.

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Section: Discussioncontrasting

confidence: 53%

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confidence: 94%

mentioning

confidence: 99%

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Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

Koukouli

Rooy

Changeux

et al. 2016

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

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“…This study showed that lesions of the mPFC, forebrain structures involved in awareness formation [31][32][33] , induce deficits in acquisition of the CR with a soft-tone CS, but not a loud-tone CS [30] . While the concept of conscious knowledge is not readily applicable to experimental animals, it is believed that the critical element that confers awareness about acquired knowledge comes from the conjoint operation of the neocortex and the hippocampal system [11] .…”

Section: Discussionmentioning

confidence: 70%

Awareness is essential for differential delay eyeblink conditioning with soft-tone but not loud-tone conditioned stimuli

Huang

et al. 2014

Neurosci. Bull.

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The role of awareness in differential delay eyeblink conditioning (DEC) remains controversial. Here, we investigated the involvement of awareness in differential DEC with a soft or a loud tone as the conditioned stimulus (CS). In the experiment, 36 participants were trained in differential DEC with a soft tone (60 dB) or a loud tone (85 dB) as the CS, paired with a corneal air-puff as the unconditioned stimulus (US). After conditioning, awareness of the relationship between the CS and the US was assessed with a 17-item true/false questionnaire. Interestingly, during differential DEC with a soft-tone CS, a higher proportion of differential conditioned responses (CRs) was evident in participants who were aware than those who were unaware. In contrast, when a loud tone was used as the CS, the proportion of differential CRs of the aware participants did not differ signifi cantly from those who were unaware over any of the blocks of 20 trials. In unaware participants, the percentage of differential CRs with a loud-tone CS was significantly higher than that with a soft-tone CS; however in participants classified as aware, the percentage of differential CRs with a loud-tone CS did not differ significantly from that with a soft-tone CS. The present findings suggest that awareness is critical for differential DEC when the delay task is rendered more diffi cult.

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“…Although the latter study does not address the involvement of a4b2 nAChRs, clinical trials investigating a4b2 agonists in disorders displaying attentional deficits, for example attention-deficit/hyperactivity disorder (ADHD), have shown promising results [32,33]. Additionally, b2 knockout mice have demonstrated attentional deficits in the five-choice serial reaction time task, which can be completely rescued upon selective re-expression of b2* nAChRs in the mPFC [34].…”

Section: Molecular Aspects Of Nachrsmentioning

confidence: 99%

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

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Nicotinic Acetylcholine Receptor β2 Subunits in the Medial Prefrontal Cortex Control Attention

Cited by 183 publications

References 28 publications

Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

Awareness is essential for differential delay eyeblink conditioning with soft-tone but not loud-tone conditioned stimuli

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

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