Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity for Rules in Primate Prefrontal Cortex

Vijayraghavan, Susheel; Major, Alex James; Everling, Stefan

doi:10.1016/j.neuron.2018.05.027

Cited by 45 publications

(52 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We currently do not know whether M1 or M2 muscarinic receptors are responsible for these effects. M1 receptors are not responsible for maintenance of working memory signals in a rule-based saccade task in DLPFC (62). The effects seen in our study might thus be mediated by M2 receptors, but it remains to be seen whether the same dependencies apply to a spatial attention task in FEF.…”

Section: Discussionmentioning

confidence: 99%

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field

Dasilva

Brandt

Gotthardt

et al. 2019

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

View full text Add to dashboard Cite

Attention is critical to high-level cognition, and attentional deficits are a hallmark of cognitive dysfunction. A key transmitter for attentional control is acetylcholine, but its cellular actions in attention-controlling areas remain poorly understood. Here we delineate how muscarinic and nicotinic receptors affect basic neuronal excitability and attentional control signals in different cell types in macaque frontal eye field. We found that broad spiking and narrow spiking cells both require muscarinic and nicotinic receptors for normal excitability, thereby affecting ongoing or stimulus-driven activity. Attentional control signals depended on muscarinic, not nicotinic receptors in broad spiking cells, while they depended on both muscarinic and nicotinic receptors in narrow spiking cells. Cluster analysis revealed that muscarinic and nicotinic effects on attentional control signals were highly selective even for different subclasses of narrow spiking cells and of broad spiking cells. These results demonstrate that cholinergic receptors are critical to establish attentional control signals in the frontal eye field in a cell type-specific manner.

show abstract

Section: Discussionmentioning

confidence: 99%

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field

Dasilva

Brandt

Gotthardt

et al. 2019

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

View full text Add to dashboard Cite

show abstract

“…In this way, tau pathology could be propagated. Thus, possible therapies involving the use of muscarinic antagonists [131, 334, 336], or agents decreasing heparin sulphation [372], are under discussion for AD therapy.…”

Section: Extracellular and Intracellular Tau – Two Sides Of One Coinmentioning

confidence: 99%

A walk through tau therapeutic strategies

Jadhav

Ávila

Schöll

et al. 2019

acta neuropathol commun

228

206

View full text Add to dashboard Cite

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer’s disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer’s disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

show abstract

“…At present, treating cognitive malfunctioning through stimulation of the cholinergic system is limited to AChE inhibitors and nicotinic/muscarinic agonists (Rowe et al, 2015). Stimulation of nicotinic (e.g., a4b2, the a5-subunit, and a7; Koukouli et al, 2017) and muscarinic (e.g., M1) receptors (Vijayraghavan et al, 2018) displays a therapy-limiting lack of specificity for individual receptors/subunits. On the other hand, neurokine-based interventions have repeatedly failed because intolerable side effects, even when applied directly to the brain (Mufson et al, 2009).…”

Section: Therapymentioning

confidence: 99%

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

et al. 2019

View full text Add to dashboard Cite

Graphical Abstract Highlights d Single-cell transcriptomes reveal a unique profile of cortical cholinergic neurons d Female-and male-derived cells show distinct neurokineinduced miRNA responses d Differentially enriched microRNA families constitute a selforganizing network d Integrative analysis identifies mir-10/mir-199 regulators of cholinergic function SUMMARYRNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male-and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

show abstract

Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity for Rules in Primate Prefrontal Cortex

Cited by 45 publications

References 87 publications

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field

A walk through tau therapeutic strategies

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

Contact Info

Product

Resources

About