Age-related shift in LTD is dependent on neuronal adenosine A(2A) receptors interplay with mGluR5 and NMDA receptors

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca(2+) influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity

α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrPC) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrPC blockade. We found that extracellular aSyn oligomers formed a complex with PrPC that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrPC and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.M.T.F., H.V.M. and J.E.C. were supported by individual grants from Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/52228/2013; SFRH/BPD/109347/2015; SFRH/BPD/87647/2012); L.V.L. and T.F.O. were supported by a grant from the Fritz Thyssen Stiftung (Az. 10.12.2.165), Germany. L.V.L. received an iMM Lisboa internal fund (BIG – Breakthrough Idea Grant) for part of the project. L.V.L. is an Investigator FCT, Portugal. T.F.O. is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany. LISBOA-01-0145-FEDER-007391, project co-financed by FEDER, POR Lisboa 2020 - Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes

Funding Information: This study was supported by Fundação para a Ciência e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds; and by Sociedade Portuguesa de Diabetologia. The authors were supported by: A.C. (FCT, PD/BD/136863/2018; ProRegeM – PhD programme, mechanisms of disease and regenerative medicine); B.F.G. (PTDC/NEU-OSD/5644/2014); L.S. (SFRH/BD/143286/2019). T.F.O. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2067/1- 390729940, and by SFB1286 (B8). Funding Information: We would like to thank the vivarium and behavioral facilities at Instituto de Medicina Molecular?Jo?o Lobo Antunes for all the support. We also thank Prof. Rosalina Fonseca, Prof. S?lvia V. Conde, Dr Rita Machado de Oliveira, Dr Nat?lia Madeira, Dr Liliana Lopes, Dr Tatiana Burrinha, and Dr Catarina Perdig?o for fruitful discussions. We thank Dr Manuela Correia for all the laboratory support. We are deeply thankful to Prof. Jos? Ramalho for kindly allowing the use of equipment for protein analysis. This study was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds; and by Sociedade Portuguesa de Diabetologia. The authors were supported by: A.C. (FCT, PD/BD/136863/2018; ProRegeM ? PhD programme, mechanisms of disease and regenerative medicine); B.F.G. (PTDC/NEU-OSD/5644/2014); L.S. (SFRH/BD/143286/2019). T.F.O. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany?s Excellence Strategy - EXC 2067/1- 390729940, and by SFB1286 (B8). Publisher Copyright: © 2022, The Author(s).Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson’s disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.publishersversionpublishe

α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrPC) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrPC blockade. We found that extracellular aSyn oligomers formed a complex with PrPC that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrPC and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.M.T.F., H.V.M. and J.E.C. were supported by individual grants from Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/52228/2013; SFRH/BPD/109347/2015; SFRH/BPD/87647/2012); L.V.L. and T.F.O. were supported by a grant from the Fritz Thyssen Stiftung (Az. 10.12.2.165), Germany. L.V.L. received an iMM Lisboa internal fund (BIG – Breakthrough Idea Grant) for part of the project. L.V.L. is an Investigator FCT, Portugal. T.F.O. is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany. LISBOA-01-0145-FEDER-007391, project co-financed by FEDER, POR Lisboa 2020 - Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat

It is well known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid (aCSF) traditionally contains relatively high concentrations of calcium (2-4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion-selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid (hCSF) to 1.0 mM of a total concentration of 1.2 mM (86%). Using patch-clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission and long-term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold and increased the rate of both de- and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2 mM calcium high-frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the aCSF has striking effects on neuronal excitability, synaptic transmission and the induction of LTP. This article is protected by copyright. All rights reserved