Pub Date : 2025-03-07DOI: 10.1016/j.nbd.2025.106863
Hila Sapir , Ghattas Bisharat , Hava Golan , Jennifer Resnik
Folate metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), is crucial for proper neurodevelopment, and disruptions—whether due to genetic polymorphisms or maternal nutritional deficits—have been linked to cognitive and behavioral impairments. Notably, MTHFR-deficient mouse models display altered social interaction and auditory communication, hinting at disruptions in auditory-related circuits and prompting the question of whether impaired folate metabolism might also affect sound processing and perception. Here, using two-photon calcium imaging, we show that MTHFR deficiency increases both spontaneous and sound-evoked activity in the auditory cortex and significantly shifts neuronal response profiles, which in turn elevates perceived loudness while reducing sound-level discrimination. These findings underscore the potential role of compromised folate metabolism in driving the atypical auditory responses and may have broader relevance for understanding sensory dysfunction in various neurodevelopmental conditions.
{"title":"Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice","authors":"Hila Sapir , Ghattas Bisharat , Hava Golan , Jennifer Resnik","doi":"10.1016/j.nbd.2025.106863","DOIUrl":"10.1016/j.nbd.2025.106863","url":null,"abstract":"<div><div>Folate metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), is crucial for proper neurodevelopment, and disruptions—whether due to genetic polymorphisms or maternal nutritional deficits—have been linked to cognitive and behavioral impairments. Notably, MTHFR-deficient mouse models display altered social interaction and auditory communication, hinting at disruptions in auditory-related circuits and prompting the question of whether impaired folate metabolism might also affect sound processing and perception. Here, using two-photon calcium imaging, we show that MTHFR deficiency increases both spontaneous and sound-evoked activity in the auditory cortex and significantly shifts neuronal response profiles, which in turn elevates perceived loudness while reducing sound-level discrimination. These findings underscore the potential role of compromised folate metabolism in driving the atypical auditory responses and may have broader relevance for understanding sensory dysfunction in various neurodevelopmental conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106863"},"PeriodicalIF":5.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-04DOI: 10.1016/j.nbd.2025.106862
Yifei Zheng , Jiahui Yang , Xuanyao Li , Linjie Qi , Zhuo Zheng , Jiming Kong , Guohui Zhang , Ying Guo
Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.
{"title":"Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration","authors":"Yifei Zheng , Jiahui Yang , Xuanyao Li , Linjie Qi , Zhuo Zheng , Jiming Kong , Guohui Zhang , Ying Guo","doi":"10.1016/j.nbd.2025.106862","DOIUrl":"10.1016/j.nbd.2025.106862","url":null,"abstract":"<div><div>Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106862"},"PeriodicalIF":5.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-02DOI: 10.1016/j.nbd.2025.106861
A. Peck , A. Dadi , Z. Yavarow , L.N. Alfano , D. Anderson , M.R. Arkin , T.F. Chou , E.S. D'Ambrosio , J. Diaz-Manera , J.P. Dudley , A.G. Elder , N. Ghoshal , C.E. Hart , M.M. Hart , D.M. Huryn , A.E. Johnson , K.B. Jones , V. Kimonis , E. Kiskinis , E.B. Lee , N. Peck
Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach.
The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.
{"title":"2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy","authors":"A. Peck , A. Dadi , Z. Yavarow , L.N. Alfano , D. Anderson , M.R. Arkin , T.F. Chou , E.S. D'Ambrosio , J. Diaz-Manera , J.P. Dudley , A.G. Elder , N. Ghoshal , C.E. Hart , M.M. Hart , D.M. Huryn , A.E. Johnson , K.B. Jones , V. Kimonis , E. Kiskinis , E.B. Lee , N. Peck","doi":"10.1016/j.nbd.2025.106861","DOIUrl":"10.1016/j.nbd.2025.106861","url":null,"abstract":"<div><div>Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the <em>VCP</em> gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach.</div><div>The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106861"},"PeriodicalIF":5.1,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-27DOI: 10.1016/j.nbd.2025.106848
Thomas Wichmann , Alexandra Nelson , Eileen Ruth S. Torres , Per Svenningsson , Roberta Marongiu
Parkinson's disease is diagnosed based on motor symptoms, but non-motor symptoms of the disease, such as cognitive impairment, autonomic dysfunction, hyposmia, sleep disorders, and psychiatric disorders heavily impact patient and caregiver quality of life. It has proven challenging to faithfully reproduce and quantify these non-motor phenotypes. Indeed, many non-motor signs in animals that may phenotypically resemble features in patients may be caused by different mechanisms or may not be consistent within the same or similar models. In this review, we survey the existing literature on the assessment of non-motor signs in parkinsonian rodents and non-human primates. We highlight the gaps in our understanding and suggest how researchers might improve experimental designs to produce more meaningful results with the hope of better understanding the disease and developing better therapies.
{"title":"Leveraging animal models to understand non-motor symptoms of Parkinson's disease","authors":"Thomas Wichmann , Alexandra Nelson , Eileen Ruth S. Torres , Per Svenningsson , Roberta Marongiu","doi":"10.1016/j.nbd.2025.106848","DOIUrl":"10.1016/j.nbd.2025.106848","url":null,"abstract":"<div><div>Parkinson's disease is diagnosed based on motor symptoms, but non-motor symptoms of the disease, such as cognitive impairment, autonomic dysfunction, hyposmia, sleep disorders, and psychiatric disorders heavily impact patient and caregiver quality of life. It has proven challenging to faithfully reproduce and quantify these non-motor phenotypes. Indeed, many non-motor signs in animals that may phenotypically resemble features in patients may be caused by different mechanisms or may not be consistent within the same or similar models. In this review, we survey the existing literature on the assessment of non-motor signs in parkinsonian rodents and non-human primates. We highlight the gaps in our understanding and suggest how researchers might improve experimental designs to produce more meaningful results with the hope of better understanding the disease and developing better therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106848"},"PeriodicalIF":5.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.
Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 Scn1a+/− DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of NaV1.1 expression.
We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.
{"title":"Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality","authors":"Lara Pizzamiglio , Fabrizio Capitano , Evgeniia Rusina , Giuliana Fossati , Elisabetta Menna , Isabelle Léna , Flavia Antonucci , Massimo Mantegazza","doi":"10.1016/j.nbd.2025.106853","DOIUrl":"10.1016/j.nbd.2025.106853","url":null,"abstract":"<div><div>Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the <em>SCN1A</em> gene (Na<sub>V</sub>1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.</div><div>Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 <em>Scn1a</em><sup><em>+/−</em></sup> DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of Na<sub>V</sub>1.1 expression.</div><div>We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106853"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1016/j.nbd.2025.106859
Mackenzie Smith , Grace E. Dodis , Amanda M. Vanderplow , Sonia Gonzalez , Yewon Rhee , Karie Scrogin , Rocco G. Gogliotti
Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MeCP2) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M1 muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M1 receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M1 is found on cholinergic interneurons, we hypothesized that M1-potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, Mecp2+/− and Mecp2+/+ mice were screened for apneas before and after administration of the M1 positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated Mecp2+/− brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that Mecp2+/− mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M1 potentiation.
{"title":"Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/− mice","authors":"Mackenzie Smith , Grace E. Dodis , Amanda M. Vanderplow , Sonia Gonzalez , Yewon Rhee , Karie Scrogin , Rocco G. Gogliotti","doi":"10.1016/j.nbd.2025.106859","DOIUrl":"10.1016/j.nbd.2025.106859","url":null,"abstract":"<div><div>Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the <em>methyl-CpG binding protein 2</em> (<em>MeCP2</em>) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M<sub>1</sub> muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M<sub>1</sub> receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M<sub>1</sub> is found on cholinergic interneurons, we hypothesized that M<sub>1</sub>-potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, <em>Mecp2</em><sup><em>+/−</em></sup> and <em>Mecp2</em><sup><em>+/+</em></sup> mice were screened for apneas before and after administration of the M<sub>1</sub> positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated <em>Mecp2</em><sup><em>+/−</em></sup> brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that <em>Mecp2</em><sup><em>+/−</em></sup> mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M<sub>1</sub> potentiation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106859"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1016/j.nbd.2025.106856
Samuel P. Brown , Achintya K. Jena , Joanna J. Osko, Joseph L. Ransdell
Loss-of-function mutations in tuberous sclerosis 1 (TSC1) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific Tsc1 deletion (Tsc1mut/mut) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in Tsc1mut/mut Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of Tsc1mut/mut Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of Tsc1mut/mut Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous Tsc1 deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to Tsc1 haploinsufficiency are delayed compared to age-matched Tsc1mut/mut Purkinje neurons. Together, these data reveal that the loss of Tsc1 impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins essential for AIS organization and function.
{"title":"Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function","authors":"Samuel P. Brown , Achintya K. Jena , Joanna J. Osko, Joseph L. Ransdell","doi":"10.1016/j.nbd.2025.106856","DOIUrl":"10.1016/j.nbd.2025.106856","url":null,"abstract":"<div><div>Loss-of-function mutations in tuberous sclerosis 1 (<em>TSC1</em>) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of <em>Tsc1</em> from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific <em>Tsc1</em> deletion (<em>Tsc1</em><sup><em>mut/mut</em></sup>) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in <em>Tsc1</em><sup><em>mut/mut</em></sup> Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of <em>Tsc1</em><sup><em>mut/mut</em></sup> Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of <em>Tsc1</em><sup><em>mut/mut</em></sup> Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous <em>Tsc1</em> deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to <em>Tsc1</em> haploinsufficiency are delayed compared to age-matched <em>Tsc1</em><sup><em>mut/mut</em></sup> Purkinje neurons. Together, these data reveal that the loss of <em>Tsc1</em> impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins essential for AIS organization and function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106856"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1016/j.nbd.2025.106857
Hu Zang, Xiaoyu Ji, Wenlong Yao, Li Wan, Chuanhan Zhang, Chang Zhu, Tongtong Liu
The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.
{"title":"Role of efferocytosis in chronic pain —— From molecular perspective","authors":"Hu Zang, Xiaoyu Ji, Wenlong Yao, Li Wan, Chuanhan Zhang, Chang Zhu, Tongtong Liu","doi":"10.1016/j.nbd.2025.106857","DOIUrl":"10.1016/j.nbd.2025.106857","url":null,"abstract":"<div><div>The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106857"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1016/j.nbd.2025.106858
Timothy O. West , Kenan Steidel , Tjalda Flessner , Alexander Calvano , Deniz Kucukahmetler , Mariëlle J. Stam , Meaghan E. Spedden , Benedikt Wahl , Veikko Jousmäki , John Eraifej , Ashwini Oswal , Tabish A. Saifee , Gareth Barnes , Simon F. Farmer , David J. Pedrosa , Hayriye Cagnan
Essential Tremor (ET) is a very common neurological disorder characterised by involuntary rhythmic movements attributable to pathological synchronization within corticothalamic circuits. Previous work has focused on tremor in isolation, overlooking broader disturbances to motor control during naturalistic movements such as reaching. We hypothesised that ET disrupts the sequential engagement of large-scale rhythmic brain networks, leading to both tremor and deficits in motor planning and execution. To test this, we performed whole-head neuroimaging during an upper-limb reaching task using high-density electroencephalography in ET patients and healthy controls, alongside optically pumped magnetoencephalography in a smaller cohort. Key motor regions—including the supplementary motor area, premotor cortex, posterior parietal cortex, and motor cerebellum—were synchronized to tremor rhythms. Patients exhibited a 15 % increase in low beta (14–21 Hz) desynchronization over the supplementary motor area during movement, which strongly correlated with tremor severity (R2 = 0.85). A novel dimensionality reduction technique revealed four distinct networks accounting for 97 % of the variance in motor-related brain-wide oscillations, with ET altering their sequential engagement. Consistent with our hypothesis, the frontoparietal beta network- normally involved in motor planning-exhibited additional desynchronization during movement execution in ET patients. This altered engagement correlated with slower movement velocities, suggesting an adaptation towards feedback-driven motor control. These findings reveal fundamental disruptions in distributed motor control networks in ET and identify novel biomarkers as targets for next-generation brain stimulation therapies.
{"title":"Essential tremor disrupts rhythmic brain networks during naturalistic movement","authors":"Timothy O. West , Kenan Steidel , Tjalda Flessner , Alexander Calvano , Deniz Kucukahmetler , Mariëlle J. Stam , Meaghan E. Spedden , Benedikt Wahl , Veikko Jousmäki , John Eraifej , Ashwini Oswal , Tabish A. Saifee , Gareth Barnes , Simon F. Farmer , David J. Pedrosa , Hayriye Cagnan","doi":"10.1016/j.nbd.2025.106858","DOIUrl":"10.1016/j.nbd.2025.106858","url":null,"abstract":"<div><div>Essential Tremor (ET) is a very common neurological disorder characterised by involuntary rhythmic movements attributable to pathological synchronization within corticothalamic circuits. Previous work has focused on tremor in isolation, overlooking broader disturbances to motor control during naturalistic movements such as reaching. We hypothesised that ET disrupts the sequential engagement of large-scale rhythmic brain networks, leading to both tremor and deficits in motor planning and execution. To test this, we performed whole-head neuroimaging during an upper-limb reaching task using high-density electroencephalography in ET patients and healthy controls, alongside optically pumped magnetoencephalography in a smaller cohort. Key motor regions—including the supplementary motor area, premotor cortex, posterior parietal cortex, and motor cerebellum—were synchronized to tremor rhythms. Patients exhibited a 15 % increase in low beta (14–21 Hz) desynchronization over the supplementary motor area during movement, which strongly correlated with tremor severity (R<sup>2</sup> = 0.85). A novel dimensionality reduction technique revealed four distinct networks accounting for 97 % of the variance in motor-related brain-wide oscillations, with ET altering their sequential engagement. Consistent with our hypothesis, the frontoparietal beta network- normally involved in motor planning-exhibited additional desynchronization during movement execution in ET patients. This altered engagement correlated with slower movement velocities, suggesting an adaptation towards feedback-driven motor control. These findings reveal fundamental disruptions in distributed motor control networks in ET and identify novel biomarkers as targets for next-generation brain stimulation therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106858"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1016/j.nbd.2025.106854
Xin Sun , Lijuan Li , Liyi Huang , Yangan Li , Lu Wang , Quan Wei
Spinal cord injury (SCI) disrupts the communication between the brain and spinal cord, resulting in the loss of motor function below the injury site. However, spontaneous structural and functional plasticity occurs in neural circuits after SCI, with unaffected synaptic inputs forming new connections and detour pathways to support recovery. The review discusses various mechanisms of circuit reorganization post-SCI, including supraspinal pathways, spinal interneurons, and spinal central pattern generators. Functional recovery may rely on maintaining a balance between excitatory and inhibitory neural activity, as well as enhancing proprioceptive input, which plays a key role in limb stability. The review emphasizes the importance of endogenous neuronal regeneration, neuromodulation therapies (such as electrical stimulation) and proprioception in SCI treatment. Future research should integrate advanced technologies such as gene targeting, imaging, and single-cell mapping to better understand the mechanisms underpinning SCI recovery, aiming to identify key neuronal subpopulations for targeted reconstruction and enhanced functional recovery. By harnessing spinal circuit reorganization, these efforts hold the potential to pave the way for more precise and effective strategies for functional recovery after SCI.
{"title":"Harnessing spinal circuit reorganization for targeted functional recovery after spinal cord injury","authors":"Xin Sun , Lijuan Li , Liyi Huang , Yangan Li , Lu Wang , Quan Wei","doi":"10.1016/j.nbd.2025.106854","DOIUrl":"10.1016/j.nbd.2025.106854","url":null,"abstract":"<div><div>Spinal cord injury (SCI) disrupts the communication between the brain and spinal cord, resulting in the loss of motor function below the injury site. However, spontaneous structural and functional plasticity occurs in neural circuits after SCI, with unaffected synaptic inputs forming new connections and detour pathways to support recovery. The review discusses various mechanisms of circuit reorganization post-SCI, including supraspinal pathways, spinal interneurons, and spinal central pattern generators. Functional recovery may rely on maintaining a balance between excitatory and inhibitory neural activity, as well as enhancing proprioceptive input, which plays a key role in limb stability. The review emphasizes the importance of endogenous neuronal regeneration, neuromodulation therapies (such as electrical stimulation) and proprioception in SCI treatment. Future research should integrate advanced technologies such as gene targeting, imaging, and single-cell mapping to better understand the mechanisms underpinning SCI recovery, aiming to identify key neuronal subpopulations for targeted reconstruction and enhanced functional recovery. By harnessing spinal circuit reorganization, these efforts hold the potential to pave the way for more precise and effective strategies for functional recovery after SCI.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106854"},"PeriodicalIF":5.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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