Progress in Neurobiology最新文献_第2页

Auditory regulation of hippocampal locomotion circuits by a non-canonical reticulo-limbic pathway 非规范网状边缘通路对海马运动回路的听觉调节

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-14 DOI: 10.1016/j.pneurobio.2025.102811

Jessica Winne , George Nascimento , Rafael Pedrosa , Margareth Nogueira , Cristiano S. Simões , Klas Kullander , Katarina E. Leão , Richardson N. Leão

{"title":"Auditory regulation of hippocampal locomotion circuits by a non-canonical reticulo-limbic pathway","authors":"Jessica Winne , George Nascimento , Rafael Pedrosa , Margareth Nogueira , Cristiano S. Simões , Klas Kullander , Katarina E. Leão , Richardson N. Leão","doi":"10.1016/j.pneurobio.2025.102811","DOIUrl":"10.1016/j.pneurobio.2025.102811","url":null,"abstract":"<div><div>The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102811"},"PeriodicalIF":6.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Eye movements organize excitability state, information coding and network connectivity in the human hippocampus 眼动组织人海马的兴奋状态、信息编码和网络连接。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-13 DOI: 10.1016/j.pneurobio.2025.102812

Marcin Leszczynski , Elizabeth Espinal , Elliot Smith , Catherine Schevon , Sameer Sheth , Charles E. Schroeder

{"title":"Eye movements organize excitability state, information coding and network connectivity in the human hippocampus","authors":"Marcin Leszczynski , Elizabeth Espinal , Elliot Smith , Catherine Schevon , Sameer Sheth , Charles E. Schroeder","doi":"10.1016/j.pneurobio.2025.102812","DOIUrl":"10.1016/j.pneurobio.2025.102812","url":null,"abstract":"<div><div>Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.</div></div><div><h3>Summary</h3><div>Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102812"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons Npas4驱动早期社会隔离对社会行为和前额叶小白蛋白神经元的影响。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-13 DOI: 10.1016/j.pneurobio.2025.102810

Keshav Jindal , Amanda Ringland , Sydney Fitzcharles , Chase Redd , Damian G. Wheeler , Laurence Coutellier

{"title":"Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons","authors":"Keshav Jindal , Amanda Ringland , Sydney Fitzcharles , Chase Redd , Damian G. Wheeler , Laurence Coutellier","doi":"10.1016/j.pneurobio.2025.102810","DOIUrl":"10.1016/j.pneurobio.2025.102810","url":null,"abstract":"<div><div>Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear. Here, we identified the neuronal-specific transcription factor Npas4 as a key player in this process. We first showed that social isolation results in aberrant adolescent developmental trajectories of Npas4 and PV expression in the prefrontal cortex (PFC) leading to prolonged downregulation of Npas4 and upregulation of PV, suggesting an Npas4-driven over-inhibition of prefrontal circuits following early social isolation. Using Npas4 knockout (KO) mice and iDISCO whole brain cFos mapping, we then further implicated Npas4-dependent reduction in prefrontal activity with appearance of sociability deficits in adulthood: Npas4 KO mice failed to show an age-increase in sociability and in activity of the anterior cingulate cortex (ACC) that we observed in wild-type mice during the transition from adolescence to adulthood. Finally, using a viral approach to restore prefrontal Npas4 expression during early adolescence, we were able to rescue the sociability deficits and aberrant expression of PV in the AAC induced by social isolation. Altogether, our findings identified Npas4 as a novel molecular mediator of early social isolation on social deficits, through the role it plays on the adolescent maturation of prefrontal PV neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102810"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice 小鼠皮质亢进性驱动垂死肌萎缩侧索硬化症的症状和病理。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-08 DOI: 10.1016/j.pneurobio.2025.102809

Mouna Haidar , Aida Viden , Christin Daniel , Brittany Cuic , Taide Wang , Marius Rosier , Doris Tomas , Samuel A. Mills , Alistair Govier-Cole , Elvan Djouma , Nirma D. Perera , Sophia Luikinga , Valeria Rytova , Samantha K. Barton , David G. Gonsalvez , Lucy M. Palmer , Catriona McLean , Matthew C. Kiernan , Steve Vucic , Bradley J. Turner

{"title":"Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice","authors":"Mouna Haidar , Aida Viden , Christin Daniel , Brittany Cuic , Taide Wang , Marius Rosier , Doris Tomas , Samuel A. Mills , Alistair Govier-Cole , Elvan Djouma , Nirma D. Perera , Sophia Luikinga , Valeria Rytova , Samantha K. Barton , David G. Gonsalvez , Lucy M. Palmer , Catriona McLean , Matthew C. Kiernan , Steve Vucic , Bradley J. Turner","doi":"10.1016/j.pneurobio.2025.102809","DOIUrl":"10.1016/j.pneurobio.2025.102809","url":null,"abstract":"<div><div>Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102809"},"PeriodicalIF":6.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interplay between circadian rhythms and epigenetics in neural stem cells and Alzheimer’s disease 神经干细胞与阿尔茨海默病中昼夜节律和表观遗传学的相互作用。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-08 DOI: 10.1016/j.pneurobio.2025.102808

Tânia Cunha Alves , Kamil Musílek , Barbara Monti

{"title":"Interplay between circadian rhythms and epigenetics in neural stem cells and Alzheimer’s disease","authors":"Tânia Cunha Alves , Kamil Musílek , Barbara Monti","doi":"10.1016/j.pneurobio.2025.102808","DOIUrl":"10.1016/j.pneurobio.2025.102808","url":null,"abstract":"<div><div>The circadian clock, as a molecular timekeeper, influences most behavioural and physiological processes. Numerous symptoms associated with neurodegenerative diseases, such as sleep disorders, anxiety, and mood alteration, are linked to circadian clock dysregulation. Dysregulation of the circadian system is increasingly implicated in the onset and progression of Alzheimer's disease, and emerging evidence highlights a bidirectional relationship between Alzheimer’s disease and circadian clock disruption. A crucial point is that the circadian clock regulates adult neurogenesis, a process that is significantly impaired in Alzheimer’s disease. Recent advancements suggest that the dynamic epigenetic mechanisms—including DNA and histone modifications as well as regulation by non-coding RNA—act as a critical regulation for circadian rhythms and neurogenesis. Therefore, research on circadian disruption and, particularly, focus on harmonising the circadian clock with neurogenesis in neurodegenerative diseases may also speed up the creation of innovative, circadian-based treatments to counteract the progress of neurological disorders from a new perspective. In this review, we explore potential epigenetic mechanisms linking the circadian system to neurodegenerative diseases, with a focus on Alzheimer’s Disease.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102808"},"PeriodicalIF":6.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Anatomo-functional organization of insular networks: From sensory integration to behavioral control” [Prog. Neurobiol. 247 (2025) 102748] “岛状神经网络的解剖功能组织：从感觉整合到行为控制”的勘误表。中国生物医学工程学报，2016(5):357 - 357。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-01 DOI: 10.1016/j.pneurobio.2025.102795

Luciano Simone , Fausto Caruana , Elena Borra , Simone Del Sorbo , Ahmad Jezzini , Stefano Rozzi , Giuseppe Luppino , Marzio Gerbella

引用次数: 0

NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes NCAM2促进APP从细胞表面靶向到含有bace1的回收内体。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-01 DOI: 10.1016/j.pneurobio.2025.102807

Grant Pfundstein , Ryan Keable , Shangfeng Hu , Muayad Al-Hadi , Maximilian Baker , Melitta Schachner , Iryna Leshchyns’ka , Vladimir Sytnyk

{"title":"NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes","authors":"Grant Pfundstein , Ryan Keable , Shangfeng Hu , Muayad Al-Hadi , Maximilian Baker , Melitta Schachner , Iryna Leshchyns’ka , Vladimir Sytnyk","doi":"10.1016/j.pneurobio.2025.102807","DOIUrl":"10.1016/j.pneurobio.2025.102807","url":null,"abstract":"<div><div>Convergence of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) in endosomes initiates the production of amyloid-β (Aβ) peptides that accumulate in brains of Alzheimer’s disease patients. APP and BACE1 are segregated in neurons, and mechanisms triggering their convergence have remained poorly understood, limiting therapeutic attempts to reduce Aβ production. Neural cell adhesion molecule 2 (NCAM2) is a cell surface localized protein, which increases Aβ levels via mechanisms that are not known. We show that APP binds to the extracellular domain of NCAM2. The intracellular domain of NCAM2 binds to the Rab11 adaptor protein Rab11-FIP5. The NCAM2/APP complex is endocytosed from the cell surface and targeted to BACE1-containing Rab11-positive recycling endosomes where it is processed. Convergence of APP with BACE1 is increased in transfected CHO cells and neurons expressing NCAM2. Consequently, the levels of amyloidogenic APP cleavage products are increased in cells expressing NCAM2. In NCAM2-deficient neurons, APP accumulates at the cell surface and in early endosomes, and APP levels in recycling endosomes are reduced. Aβ production is increased by Aβ oligomers and neuronal activity, and we show that the binding of NCAM2 to APP is increased in neurons treated with Aβ oligomers or after activation of synaptic NMDA receptors. Together, our data indicate that NCAM2 binds to APP and promotes APP targeting from the neuronal cell surface to recycling endosomes where APP is cleaved by BACE1. This novel mechanism regulating the convergence of APP and BACE1 in neurons can contribute to Aβ accumulation in Alzheimer’s disease.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102807"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Astrocyte-interneuron interplay tunes neuronal excitability by enhancing the slow Ca2 + -activated K+ current 星形胶质细胞-神经元间相互作用通过增强缓慢的Ca2 +激活的K+电流来调节神经元的兴奋性

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-16 DOI: 10.1016/j.pneurobio.2025.102806

Sara Expósito , Samuel Alberquilla , Eduardo D. Martín

{"title":"Astrocyte-interneuron interplay tunes neuronal excitability by enhancing the slow Ca2 + -activated K+ current","authors":"Sara Expósito , Samuel Alberquilla , Eduardo D. Martín","doi":"10.1016/j.pneurobio.2025.102806","DOIUrl":"10.1016/j.pneurobio.2025.102806","url":null,"abstract":"<div><div>Neurons have the unique ability to integrate synaptic information by modulating the function of the voltage-gated membrane ion channels, which govern their excitability. Astrocytes play active roles in synaptic function, from synapse formation and maturation to plasticity processes. However, it remains elusive whether astrocytes can impact the neuronal activity by regulating membrane ionic conductances that control the intrinsic firing properties. Here, we found that astrocytes enhance the slow Ca<sup>2+</sup>-activated K<sup>+</sup> current (sIAHP) in CA1 hippocampal pyramidal neurons through the release of adenosine. Remarkably, our results indicate that interneuron activity plays a crucial role in this astrocyte-mediated modulation of sIAHP. Specifically, optogenetically stimulated hippocampal interneurons were found to evoke coordinated signaling between astrocytes and pyramidal neurons, relying on the activation of GABA<sub>B</sub> and adenosine A1 receptors. In addition, the selective genetic ablation of GABA<sub>B</sub> receptors in CA1 astrocytes prevented the potentiation of sIAHP and spike frequency adaptation in pyramidal cells following interneuron activation. Therefore, our data reveal the capability of astrocytes to modulate the intrinsic membrane properties that dictate neuronal firing rate, which in turn governs hippocampal network activity.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102806"},"PeriodicalIF":6.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states 颗粒状脾后皮层细胞类型特异性胆碱能控制与大脑状态角速度编码的含义。

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-08 DOI: 10.1016/j.pneurobio.2025.102804

Izabela Jedrasiak-Cape , Chloe Rybicki-Kler , Isla Brooks , Megha Ghosh , Ellen K.W. Brennan , Sameer Kailasa , Tyler G. Ekins , Alan Rupp , Omar J. Ahmed

{"title":"Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states","authors":"Izabela Jedrasiak-Cape , Chloe Rybicki-Kler , Isla Brooks , Megha Ghosh , Ellen K.W. Brennan , Sameer Kailasa , Tyler G. Ekins , Alan Rupp , Omar J. Ahmed","doi":"10.1016/j.pneurobio.2025.102804","DOIUrl":"10.1016/j.pneurobio.2025.102804","url":null,"abstract":"<div><div>Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type – the low-rheobase (LR) neuron – has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102804"},"PeriodicalIF":6.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tcf4 Deficiency causes recurrent seizures in mice Tcf4缺乏导致小鼠复发性癫痫发作

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-04 DOI: 10.1016/j.pneurobio.2025.102805

Laura Craciun , Vivianna R. DeNittis , Matthew T. Davis , Jeanne T. Paz , Kaoru Saijo

{"title":"Tcf4 Deficiency causes recurrent seizures in mice","authors":"Laura Craciun , Vivianna R. DeNittis , Matthew T. Davis , Jeanne T. Paz , Kaoru Saijo","doi":"10.1016/j.pneurobio.2025.102805","DOIUrl":"10.1016/j.pneurobio.2025.102805","url":null,"abstract":"<div><div>Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of <em>TCF4</em> due to deletions or mutations causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures, autism, and intellectual disability. Previous studies have shown that various mutations, including deletion of exon 4 in the mouse <em>Tcf4</em> gene in neural progenitors, neurons, or oligodendrocytes, did not reproduce the seizure phenotype. Here, we report that mice with a heterozygous deletion of <em>Tcf4</em> in Aldehyde Dehydrogenase 1 Family Member L1 (<em>Aldh1l1</em>)-expressing cells—which resulted in approximately 60 % reduced <em>Tcf4</em> expression in astrocytes and a 35 % reduction in other cell types, including neurons and oligodendrocytes—developed astrogliosis as early as postnatal day 4, followed by severe recurrent seizures beginning at three months of age or later, and exhibited shortened lifespans. Additionally, these mice showed increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus in adulthood. Furthermore, single-nucleus RNA sequencing revealed widespread gene expression changes, including genes associated with epilepsy, in excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes in our PTHS mouse model compared to wild-type controls. Overall, this is the first report of a PTHS mouse model exhibiting seizures, providing a valuable tool to investigate the mechanisms underlying PTHS pathogenesis and to develop therapies for PTHS and its associated epilepsy.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102805"},"PeriodicalIF":6.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0