During the last decades,advances in the understanding of genetic,cellular,and microstructural alterations associated to Huntington's disease(HD)have improved the understanding of this progressive and fatal illness...During the last decades,advances in the understanding of genetic,cellular,and microstructural alterations associated to Huntington's disease(HD)have improved the understanding of this progressive and fatal illness.However,events related to early neuropathological events,neuroinflammation,deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown.Ultra-high field diffusion MRI(UHFD-MRI)techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD.In addition,it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers.Moreover,qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events,compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration.The application of ultra-high field diffusion-MRI technology in animal models,particularly the R6/1 mice(a common preclinical mammalian model of HD),provide the opportunity to analyze alterations in a physiologically intact model of the disease.Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented,further application of different diffusion MRI techniques used in combination like diffusion tensor imaging,and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter.Thus,the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.展开更多
γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is respo...γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.展开更多
Background Dysregulation of the endocannabinoid system(eCBS)and the loss of CB1 receptors(CB1R)in the basal ganglia are well-established hallmarks of Huntington’s disease(HD).As a result,significant research efforts ...Background Dysregulation of the endocannabinoid system(eCBS)and the loss of CB1 receptors(CB1R)in the basal ganglia are well-established hallmarks of Huntington’s disease(HD).As a result,significant research efforts have focused on targeting the eCBS to alleviate motor disturbances associated with the disease.Beyond its role in motor control,the eCBS is a complex signaling network critically involved in regulating learning and memory.Despite this,the potential involvement of eCBS dysfunction in the cognitive decline characteristic of HD,often manifested well before motor dysfunction,has remained largely unexplored.Methods CB1R expression in the hippocampus was evaluated in both human HD samples and HD mouse models(R6/1 and HdhQ7/Q111 models,including both sexes)using Western blotting,immunohistochemistry,and radioligand binding assays.To restore CB1R function,CB1R agonist WIN-55212–2 was systemically administered,or viral vectors encoding CB1R were locally infused into the hippocampus of HD mice.A multidisciplinary approach combining behavioral,biochemical,electrophysiological,and morphological analyses,was employed to investigate the molecular mechanisms underlying the effects of CB1R activation in the context of HD-related cognitive dysfunction.Results In both human HD samples and HD mouse models,CB1R protein levels were reduced in the hippocampus,accompanied by structural synaptic alterations and impairment in spatial,recognition and working memory.Moreover,hippocampal depolarization-induced suppression of inhibition was significantly disrupted in R6/1 mice.Administration of WIN-55212–2 successfully restored these synaptic and cognitive deficits.Immunohistochemical analysis revealed that the CB1R decrease was specifically localized to GABAergic interneurons within the hippocampus.Notably,targeted restoration of CB1R expression in these interneurons via viral vector delivery was sufficient to rescue hippocampal-dependent memory deficits in HD mice.Conclusion This study suggests that impaired CB1R function in hippocampal GABAergic interneurons contributes to memory dysfunction in HD.展开更多
基金supported in part by the High Magnetic Field Laboratory(NHMFL)and Advanced Magnetic Resonance Imaging and Spectroscopy(AMRIS)under Magnetic Laboratory Visiting Scientist Program Award,No.VSP#327(to RG)。
文摘During the last decades,advances in the understanding of genetic,cellular,and microstructural alterations associated to Huntington's disease(HD)have improved the understanding of this progressive and fatal illness.However,events related to early neuropathological events,neuroinflammation,deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown.Ultra-high field diffusion MRI(UHFD-MRI)techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD.In addition,it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers.Moreover,qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events,compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration.The application of ultra-high field diffusion-MRI technology in animal models,particularly the R6/1 mice(a common preclinical mammalian model of HD),provide the opportunity to analyze alterations in a physiologically intact model of the disease.Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented,further application of different diffusion MRI techniques used in combination like diffusion tensor imaging,and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter.Thus,the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.
基金the programs for the postdoctoral fellowships-Chilean CONICYT-FONDECYT#3140218,Mexican CONACYT#164978 and DID-UACh S-2015-81Sistema Nacional de Investigadores#58512 to Abraham Rosas-Arellano+2 种基金supported by USACH PhD fellowshipsupported with a PhD fellowship from CONACYT(#299627)FONDECYT grants 1151206 and 1110571 to Maite A.Castro
文摘γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.
基金supported by the Spanish Ministerio de Ciencia e Innovación(PID2021-123732OB-I00 to SG,PID2021-125118OB-I00 to MG,PID2019-106579RB-I00,and PID2022-142617NB-I00 to GP,and PID2022-141700OB-I00 to AB funded by MCIN/AEI/https://doi.org/10.13039/501100011033)Fundacio la Marato de TV3(202013-30-31-32 to SG,MG and GP)+4 种基金AGAUR Generalitat de Catalunya(2021-SGR-01358 to AB and 2021-SGR 01086 to SG)grants to R.R.-P.from the Basque Government IT1454-22 to the“Neurochemistry and Neurodegeneration”consolidated research groupInstituto de Salud Carlos III through the project PI20/00153(co-funded by European Regional Development Fund“A way to make Europe”)by BIOEF through the project BIO22/ALZ/010 funded by Eitb Maratoia.A P-V is the recipient of a PRE2022-101764 fellowship(PID2021-123732OB-I00)I.B.d.T.is the recipient of an Investigo fellowship funded by the European Union-Next Generation EU.
文摘Background Dysregulation of the endocannabinoid system(eCBS)and the loss of CB1 receptors(CB1R)in the basal ganglia are well-established hallmarks of Huntington’s disease(HD).As a result,significant research efforts have focused on targeting the eCBS to alleviate motor disturbances associated with the disease.Beyond its role in motor control,the eCBS is a complex signaling network critically involved in regulating learning and memory.Despite this,the potential involvement of eCBS dysfunction in the cognitive decline characteristic of HD,often manifested well before motor dysfunction,has remained largely unexplored.Methods CB1R expression in the hippocampus was evaluated in both human HD samples and HD mouse models(R6/1 and HdhQ7/Q111 models,including both sexes)using Western blotting,immunohistochemistry,and radioligand binding assays.To restore CB1R function,CB1R agonist WIN-55212–2 was systemically administered,or viral vectors encoding CB1R were locally infused into the hippocampus of HD mice.A multidisciplinary approach combining behavioral,biochemical,electrophysiological,and morphological analyses,was employed to investigate the molecular mechanisms underlying the effects of CB1R activation in the context of HD-related cognitive dysfunction.Results In both human HD samples and HD mouse models,CB1R protein levels were reduced in the hippocampus,accompanied by structural synaptic alterations and impairment in spatial,recognition and working memory.Moreover,hippocampal depolarization-induced suppression of inhibition was significantly disrupted in R6/1 mice.Administration of WIN-55212–2 successfully restored these synaptic and cognitive deficits.Immunohistochemical analysis revealed that the CB1R decrease was specifically localized to GABAergic interneurons within the hippocampus.Notably,targeted restoration of CB1R expression in these interneurons via viral vector delivery was sufficient to rescue hippocampal-dependent memory deficits in HD mice.Conclusion This study suggests that impaired CB1R function in hippocampal GABAergic interneurons contributes to memory dysfunction in HD.
