Hyperexcitability and Homeostasis in Fragile X Syndrome DOI Creative Commons
Xiaopeng Liu, Vipendra Kumar, Nien‐Pei Tsai

и другие.

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Янв. 6, 2022

Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from mutation in the FMR1 gene subsequent loss its protein product FMRP. Despite this simple genetic origin, FXS phenotypically complex disorder with range physical neurocognitive disruptions. While numerous molecular cellular pathways are affected by FMRP loss, there growing evidence that circuit hyperexcitability may be common convergence point can account for many wide-ranging phenotypes seen FXS. The mechanisms include alterations to excitatory synaptic function connectivity, reduced inhibitory neuron activity, as well changes ion channel expression conductance. However, understanding impact on complicated inherent plasticity neural circuits, which display an array homeostatic maintain activity near set levels. also important regulator activity-dependent brain, meaning dysregulated both consequence hyperexcitable networks This makes it difficult separate direct effects myriad pleiotropic compensatory associated it, likely contribute pathophysiology. Here we will: (1) review models, focusing similarities/differences across brain regions, cell-types, developmental time points; (2) examine how excitability disruptions interact each other ultimately dysfunction FXS; (3) discuss these deficits disease-relevant behavioral like epilepsy sensory hypersensitivity. Through discussion where current field stands, aim introduce perspectives moving forward research.

Язык: Английский

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing DOI
Stephen C. Cunnane, Eugenia Trushina, Cecilie Morland

и другие.

Nature Reviews Drug Discovery, Год журнала: 2020, Номер 19(9), С. 609 - 633

Опубликована: Июль 24, 2020

Язык: Английский

Процитировано

695

Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease DOI

Boaz Styr,

Inna Slutsky

Nature Neuroscience, Год журнала: 2018, Номер 21(4), С. 463 - 473

Опубликована: Фев. 5, 2018

Язык: Английский

Процитировано

282

GABAA receptors: structure, function, pharmacology, and related disorders DOI Creative Commons
Amr Ghit,

Dina Assal,

Ahmed S. Al‐Shami

и другие.

Journal of Genetic Engineering and Biotechnology, Год журнала: 2021, Номер 19(1), С. 123 - 123

Опубликована: Авг. 21, 2021

γ-Aminobutyric acid sub-type A receptors (GABAARs) are the most prominent inhibitory neurotransmitter in CNS. They a family of ligand-gated ion channel with significant physiological and therapeutic implications.GABAARs heteropentamers formed from selection 19 subunits: six α (alpha1-6), three β (beta1-3), γ (gamma1-3), ρ (rho1-3), one each δ (delta), ε (epsilon), π (pi), θ (theta) which result production considerable number receptor isoforms. Each isoform exhibits distinct pharmacological properties. However, majority GABAARs composed two subunits, subunit arranged as γ2β2α1β2α1 counterclockwise around center. The mature has central chloride gated by GABA modulated variety different drugs. Changes synthesis or release may have effect on normal brain function. Furthermore, molecular interactions effects caused drugs extremely complex. This is due to structural heterogeneity receptors, existence multiple allosteric binding sites well wide range ligands that can bind them. Notably, dysfunction GABAergic system contributes development several diseases. Therefore, understanding relationship between GABAA deficits CNS disorders thus impact discovery disease pathogenesis drug development.To date, few reviews discussed detail. Accordingly, this review aims summarize current structural, physiological, properties GABAARs, shedding light common associated disorders.

Язык: Английский

Процитировано

258

Modifiable Risk Factors for Alzheimer’s Disease DOI Creative Commons
George A. Edwards, Nazaret Gamez, Gabriel Escobedo

и другие.

Frontiers in Aging Neuroscience, Год журнала: 2019, Номер 11

Опубликована: Июнь 24, 2019

Since first described in the early 1900s, Alzheimer's disease (AD) has risen exponentially prevalence and concern. Research still drives to understand etiology pathogenesis of this what risk factors can attribute AD. With a majority AD cases being sporadic origin, increasing exponential growth an aged population lack treatment, it is imperative discover easy accessible preventative method for Some increase propensity such as aging, sex, genetics. Moreover, there are also modifiable factors-in terms treatable medical conditions lifestyle choices-that play role developing These have their own biological mechanisms that may contribute pathological consequences. In review article, we will discuss current literature how each these interplay into development progression if strategically analyzed treated, could aid protection against neurodegenerative disease.

Язык: Английский

Процитировано

224

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease DOI Creative Commons
Sara Hijazi, Tim S. Heistek, Philip Scheltens

и другие.

Molecular Psychiatry, Год журнала: 2019, Номер 25(12), С. 3380 - 3398

Опубликована: Авг. 20, 2019

Abstract Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal memory impairment APP/PS1 mice, a mouse model increased amyloidosis. We demonstrate PV become hyperexcitable at ~16 weeks age, when no changes are observed yet the intrinsic properties pyramidal cells. This state coincides with transmission onto neurons deficits spatial learning memory. treatment aimed preventing from becoming sufficient restore interneuron wild-type levels, reduce input cells, rescue mice. Importantly, intervention restoring activity has long-term beneficial effects on activity, reduces amyloid plaque deposition, hallmark AD pathology. Taken together, these findings suggest hyperactivity might be clinically relevant decline delaying progression.

Язык: Английский

Процитировано

168

PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model DOI Creative Commons
Neta Rosenzweig,

Raz Dvir-Szternfeld,

Afroditi Tsitsou-Kampeli

и другие.

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Янв. 28, 2019

Abstract Alzheimer’s disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke sequence of responses that lead modification. Here, PD-L1, PD-1 ligand, found have similar efficacy modification, both animal models AD and tauopathy. Targeting PD-L1 tau-driven resulted increased immunomodulatory monocyte-derived macrophages within brain parenchyma. Single RNA-seq revealed homing expressed unique scavenger molecules including macrophage 1 (MSR1), which here be required for effect blockade Overall, our results demonstrate checkpoint targeting PD-1/PD-L1 leads modification common factors go awry dementia, thus can potentially provide immunotherapy help combat these diseases.

Язык: Английский

Процитировано

162

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment DOI Creative Commons

Yilan Xu,

Man-Na Zhao,

Yuying Han

и другие.

Frontiers in Neuroscience, Год журнала: 2020, Номер 14

Опубликована: Июнь 30, 2020

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically amyloid plaques, neuronal loss, neurofibrillary tangles. Abnormal β-protein (Aβ) deposition in the brain often thought of as major initiating factor AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, decreases synaptic glutamatergic transmission decrease neural network activity. Furthermore, there now evidence suggesting that activity aberrantly increased patients animal models due functional decreased GABA interneurons, contributing deficits. Here we describe roles played excitatory neurons Aβ-induced how altered regulate We also comprehensively review recent studies on receptors can be exploited for therapeutic benefit. an emerging target AD, with further clinical trials urgently warranted.

Язык: Английский

Процитировано

156

Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders DOI Creative Commons
Ege T. Kavalali, Lisa M. Monteggia

Neuron, Год журнала: 2020, Номер 106(5), С. 715 - 726

Опубликована: Июнь 1, 2020

Язык: Английский

Процитировано

152

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease DOI Creative Commons
Sam Harris, Fred Wolf, Bart De Strooper

и другие.

Neuron, Год журнала: 2020, Номер 107(3), С. 417 - 435

Опубликована: Июнь 23, 2020

Язык: Английский

Процитировано

143

Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways DOI Creative Commons
Pranav Preman,

María Alfonso-Triguero,

Elena Alberdi

и другие.

Cells, Год журнала: 2021, Номер 10(3), С. 540 - 540

Опубликована: Март 4, 2021

Astrocytes perform a wide variety of essential functions defining normal operation the nervous system and are active contributors to pathogenesis neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states associated with specific stages Alzheimer´s disease. The advent transcriptomics technologies enables rapid progress in characterisation pathological states. In this review, we an overview origin, main functions, molecular morphological features astrocytes physiological well conditions related We will also explore roles disease summarize transcriptional changes altered pathways observed during course

Язык: Английский

Процитировано

113