Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein

Tweedy, Clare; Kindred, Nathan; Curry, J.A.; Williams, Christopher; Taylor, John‐Paul; Atkinson, Peter J.; Randall, Fiona; Erskine, Daniel; Morris, Christopher M.; Reeve, Amy K.; Clowry, Gavin J.; LeBeau, Fiona E. N.

doi:10.1016/j.nbd.2020.105226

Cited by 16 publications

(21 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The neuropathological hallmarks of AD are the presence of extracellular senile plaques, which are mainly built of aggregates of Aβ and the neuronal presence of neurofibrillary tangles (NFT), consisting mostly of the hyperphosphorylated microtubule-associated protein (MAP) Tau. However, in AD brains, other proteinopathies exist with high frequency [44] and may also influence neurotransmitters signaling, including glutamate and GABA, and their role in the microglia-neuron communication/interaction [45][46][47][48]. Aβ peptides significantly influence glutamatergic and GABAergic neurotransmission and the level of these compounds and may be responsible for disturbances of learning and memory processes [49,50].…”

Section: The Role Of Aβ Peptides and Other Proteins With Altered Conformations In The Neuron-microglia Dialogue In Ad And Neuroinflammatimentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

View full text Add to dashboard Cite

The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

show abstract

Section: The Role Of Aβ Peptides and Other Proteins With Altered Conformations In The Neuron-microglia Dialogue In Ad And Neuroinflammatimentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Clinical studies report upregulated α-syn expression in epileptic patients, highlighting the possibility of α-syn-mediated neurodegeneration in epilepsy [ 24 , 25 ]. In addition to evidence from clinical studies, emerging preclinical data highlight a possible correlation between α-syn and epileptic seizures [ 26 , 27 ], but whether hyperexcitability is a consistent feature of early α-syn pathology is still unclear to date [ 28 - 30 ]. All these findings have increased the attention on neurodegenerative proteins, as possible targets to develop a promising therapeutic approach against epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Epilepsy and Alzheimer’s Disease: Current Concepts and Treatment Perspective on Two Closely Related Pathologies

Leo

Tallarico

Sciaccaluga

et al. 2022

View full text Add to dashboard Cite

The literature of epileptic seizures in Alzheimer's disease has significantly increased over the past decades. Remarkably, several studies suggest a bi-directional link between these two common neurological diseases, with either condition carrying a nearly 2-fold risk of contracting the other in comparison to healthy subjects. In this respect, evidence from both clinical and preclinical studies indicate that epileptogenesis and neurodegeneration possibly share common underlying mechanisms. However, the precise association between epileptogenesis and neurodegeneration still needs to be fully elucidated. Targeted intervention to reduce abnormal network hyperexcitability might constitute a therapeutic strategy to postpone the onset of later neurodegenerative changes and consequent cognitive decline by many years in patients. By virtue of this, an early diagnosis and treatment of seizures in patients with Alzheimer’s diseases should be pursued. To date, no guidelines are available for treating epileptic activity in this context, largely due to the paucity of studies sufficient to answer this question. Accordingly, clinical trials are mandatory, not only to inform clinicians about symptomatic management of seizures, in Alzheimer’s disease patients, but also to detect if a treatment with antiseizure medications could have disease-modifying effects. Moreover, it will be fundamental to expand the application of animal models of Alzheimer’s disease to comorbid conditions such as epilepsy both to reveal the mechanisms underlying seizure onset and to better define their role in cognitive decline. Such models could be also useful to identify pharmacological compounds therapeutically effective as well as reliable early biomarkers for seizures in Alzheimer’s Disease.

show abstract

“…2e). Of note, adolescent mice injected with the toxin 6-OHDA exhibit a similar ambulatory hyperactivity prior to neuronal death 91,92 , and LRRK2-overexpressing mice 93 , Parkin-deficient mice 94 , and A30P alpha-synuclein-overexpressing mice 95 all exhibit increases in DA or ambulatory hyperactivity with no observed cell loss. Increased DA availability has been proposed as a possible contributor to synaptic toxicity 96 and could be responsible for enhanced synaptic loss with Esrrg deficiency with PFF treatment.…”

Section: Discussionmentioning

confidence: 97%

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Fox

McMeekin

Savage

et al. 2022

npj Parkinsons Dis.

View full text Add to dashboard Cite

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

show abstract

Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein

Cited by 16 publications

References 65 publications

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Epilepsy and Alzheimer’s Disease: Current Concepts and Treatment Perspective on Two Closely Related Pathologies

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Contact Info

Product

Resources

About