Neurobiology of Disease最新文献

{"title":"Whole transcriptome analysis of unmutated sporadic ALS patients' peripheral blood reveals phenotype-specific gene expression signature.","authors":"Francesca Dragoni, Maria Garofalo, Rosalinda Di Gerlando, Bartolo Rizzo, Matteo Bordoni, Eveljn Scarian, Camilla Viola, Veronica Bettoni, Giuseppe Fiamingo, Danilo Tornabene, Lucia Scanu, Orietta Pansarasa, Luca Diamanti, Stella Gagliardi","doi":"10.1016/j.nbd.2025.106823","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106823","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder. According to clinical criteria, ALS patients can be classified into eight subgroups: classic, bulbar, pyramidal, pure lower motor neuron, flail arm, pure upper motor neuron, flail leg, and respiratory. There are no well-established molecular biomarkers for early diagnosis, prognosis, and progression monitoring of this fatal disease. Classification based on clinical phenotypes could be associated with peculiar gene expression patterns shaped during lifespan, allowing the identification of specific sporadic ALS (sALS) subtypes with less heterogeneous clinical and biological features. Our objective was to define a phenotype-specific transcriptomic signature of distinct ALS phenotypes, and lay the foundation for biomarkers development. We characterized 48 sALS patients by clinical and paraclinical parameters, and subdivided them in \"Classic\" (n = 12), \"Bulbar\" (n = 10), \"Flail Arm\" (n = 7), \"Flail Leg\" (n = 10) and \"Pyramidal\" (n = 9) phenotypes. RNAs extracted from patients' PBMCs and 19 controls were sequenced. Our analysis allowed the visualization of gene expression differential clusters between patients and controls. Interestingly, only one gene (Y3_RNA, a misc_RNA component of the Ro60 ribonucleoprotein involved in cellular response to interferon-alpha) was upregulated at different levels across all phenotypes, whereas other genes appeared phenotype-specific. The work proposed stress the innovative view of ALS as a multi-systemic disorder rather than a pure motor neuron-associated and 'neurocentric' pathology. The possibility to cluster ALS patients based on their molecular signature pave the way for future personalized clinical trials and early diagnosis.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106823"},"PeriodicalIF":5.1,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188783","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}

{"title":"Network-wide effects of pallidal deep brain stimulation normalised abnormal cerebellar cortical activity in the dystonic animal model.","authors":"Fabiana Santana Kragelund, Konstantinos Spiliotis, Marco Heerdegen, Tina Sellmann, Henning Bathel, Anika Lüttig, Angelika Richter, Jens Starke, Rüdiger Köhling, Denise Franz","doi":"10.1016/j.nbd.2024.106779","DOIUrl":"10.1016/j.nbd.2024.106779","url":null,"abstract":"<p><strong>Background: </strong>Deep brain stimulation (DBS) targeting globus pallidus internus (GPi) is a recognised therapy for drug-refractory dystonia. However, the mechanisms underlying this effect are not fully understood. This study explores how pallidal DBS alters spatiotemporal pattern formation of neuronal dynamics within the cerebellar cortex in a dystonic animal model, the dt^sz hamster.</p><p><strong>Methods: </strong>We conducted in vitro analysis using a high-density microelectrode array (HD-MEA) in the cerebellar cortex. For investigating the spatiotemporal pattern, mean firing rates (MFR), interspike intervals (ISI), spike amplitudes, and cerebellar connectivity among healthy control hamsters, dystonic dt^sz hamsters, DBS- and sham-DBS-treated dt^sz hamsters were analysed. A nonlinear data-driven method characterised the low-dimensional representation of the patterns in MEA data.</p><p><strong>Results: </strong>Our HD-MEA recordings revealed reduced MFR and spike amplitudes in the dt^sz hamsters compared to healthy controls. Pallidal DBS induced network-wide effects, normalising MFR, spike amplitudes, and connectivity measures in hamsters, thereby countervailing these electrophysiological abnormalities. Additionally, network analysis showed neural activity patterns organised into communities, with higher connectivity in both healthy and DBS groups compared to dt^sz.</p><p><strong>Conclusions: </strong>These findings suggest that pallidal DBS exerts some of its therapeutic effects on dystonia by normalising neuronal activity within the cerebellar cortex. Our findings of reduced MFR and spike amplitudes in the dt^sz hamsters could be a hint of a decrease in neuronal fibres and synaptic plasticity. Treatment with pallidal DBS led to cerebellar cortical activity similar to healthy controls, displaying the network-wide impact of local stimulation.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"106779"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895826","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}

{"title":"B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury.","authors":"Vanessa O Torres, Jadwiga Turchan-Cholewo, Mary K Colson, Pavel Yanev, Daimen R S Britsch, Katherine Cotter, Annabel McAtee, Thomas Ujas, Domenico Mercurio, Xiangmei Kong, Erik J Plautz, Chaitanya R Joshi, Takeshi K Matsui, Eiichiro Mori, Ambar Cajigas-Hernandez, Kielen Zuurbier, Steve Estus, Mark P Goldberg, Nancy L Monson, Ann M Stowe","doi":"10.1016/j.nbd.2025.106819","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106819","url":null,"abstract":"<p><p>Following stroke, B cells enter brain regions outside of the ischemic injury to mediate functional recovery. Although B cells produce neurotrophins that support remote plasticity, including brain-derived neurotrophic factor (BDNF), it remains unclear which signal(s) activate B cells in the absence of infarct-localized pro-inflammatory cues. Activation of N-methyl-d-aspartate (NMDA)-type receptor (NMDAR) subunits on neurons can upregulate mature BDNF (mBDNF) production from a pro-BDNF precursor, but whether this occurs in B cells is unknown. We identified GluN2A and GluN2B NMDAR subunits on B cells that respond to glutamate and mediate nearly half of the glutamate-induced Ca²⁺ responses in activated B cell subsets. Ischemic stroke recruits GluN2A⁺ B cells into the ipsilesional hemisphere and both stroke and neurophysiologic levels of glutamate regulate gene and surface expression. Regardless of injury, pro-BDNF⁺ B localize to spleen/circulation whereas mBDNF⁺ B cells localize to the brain, including in aged male and female mice. We confirmed B cell-derived BDNF was required for in vitro and in vivo B cell-mediated neuroprotection. Lastly, GluN2A, GluN2B, glutamate-induced Ca²⁺ responses, and BDNF expression were all clinically confirmed in B cells from healthy donors, with BDNF⁺ B cells present in post-stroke human parenchyma. These data suggest that B cells express functional NMDARs that respond to glutamate, enhance NMDAR signaling with activation, and upregulate mature BDNF expression within the brain. This study identifies potential glutamate-induced neurotrophic roles for B cells in the brain; an immune response to neurotransmitters unique from established pro-inflammatory stimuli and relevant to any CNS-localized injury or disease.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106819"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123273","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}

{"title":"CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model.","authors":"Lei Wan, Ping Zhong, Pei Li, Yong Ren, Wei Wang, Mingjun Yu, Henry Y Feng, Zhen Yan","doi":"10.1016/j.nbd.2025.106826","DOIUrl":"10.1016/j.nbd.2025.106826","url":null,"abstract":"<p><p>GABAergic signaling in the brain plays a key role in regulating synaptic transmission, neuronal excitability, and cognitive processes. Large-scale sequencing has revealed the diminished expression of GABA-related genes in Alzheimer's disease (AD), however, it is largely unclear about the epigenetic mechanisms that dysregulate the transcription of these genes in AD. We confirmed that GABA synthesizing enzymes, GAD1 and GAD2, were significantly downregulated in prefrontal cortex (PFC) of AD human postmortem tissues. A tauopathy mouse model also had the significantly reduced expression of GABA-related genes, as well as the diminished GABAergic synaptic transmission in PFC pyramidal neurons. To elevate endogenous Gad1 levels, we used the CRISPR/Cas9-based epigenome editing technology to recruit histone acetyltransferase p300 to Gad1. Cells transfected with a fusion protein consisting of the nuclease-null dCas9 protein and the catalytic core of p300 (dCas9^p300), as well as a guide RNA targeting Gad1 promoter (gRNA^Gad1), had significantly increased Gad1 mRNA expression and histone acetylation at Gad1 promoter. Furthermore, the tauopathy mouse model with PFC injection of dCas9^p300 and gRNA^Gad1 lentiviruses had significantly elevated GABAergic synaptic currents and improved spatial memory. These results have provided an epigenetic editing-based gene-targeting strategy to restore synaptic inhibition and cognitive function in AD and related disorders.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106826"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079907","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}

{"title":"Spectral and coupling characteristics of somatosensory cortex and centromedian thalamus differentiate between pre- and inter-ictal 5-9 Hz oscillations in a genetic rat model of absence epilepsy.","authors":"Eleni Nikalexi, Vladimir Maksimenko, Thomas Seidenbecher, Thomas Budde, Hans-Christian Pape, Annika Lüttjohann","doi":"10.1016/j.nbd.2024.106777","DOIUrl":"10.1016/j.nbd.2024.106777","url":null,"abstract":"<p><p>Spike-wave-discharges (SWD) are the electrophysiological hallmark of absence epilepsy. SWD are generated in the thalamo-cortical network and a seizure onset zone was identified in the somatosensory cortex (S1). We have shown before that inhibition of the centromedian thalamic nucleus (CM) in GAERS rats resulted in a selective suppression of the spike component while rhythmic cortical 5-9 Hz oscillations remained present. Such oscillations are often seen to precede SWD activity in this well-validated genetic rat model of absence epilepsy, but are also seen in seizure-free periods. The present study characterizes the profile of 5-9 Hz oscillations in thalamo-cortical circuits during pre- and inter-ictal states. Here we recorded local-field-potentials in S1, CM and the secondary motor cortex of GAERS. Time-frequency analysis was used to assess spectral power and non-linear-association analysis was used to determine coupling strength and directionality between brain areas. Phase-specific electrical stimulation was used to compare cortical excitability and to assess the risk for epileptic afterdischarges. Coupling strength and spectral power were higher for the inter-ictal compared to the pre-ictal 5-9 Hz oscillations. However, coupling strength during pre-ictal oscillations was higher than during passive wakefulness. Double pulse stimulation during 5-9 Hz oscillations was more likely to induce epileptic afterdischarges compared to stimulation during passive wakefulness. While no overall differences in cortical excitability were revealed, phase-specific differences in excitability were noticed during the oscillation. Our findings indicate that intermediate coupling between S1 and CM favors SWD generation, thereby adding to the previous notion that 5-9 Hz oscillations represent high-risk periods for seizure generation. In general, pre-ictal oscillations display a unique electrophysiological profile in GAERS that might pave the way for qualification as biomarker for SWD generation and seizure prediction.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106777"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895825","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}

{"title":"Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy.","authors":"Miaomiao Mao, Nikola Jancovski, Yafit Kushner, Lucas Teasdale, Phan Truong, Kun Zhou, Samuel Reid, Linghan Jia, Ye Htet Aung, Melody Li, Christopher A Reid, Sean Byars, Ingrid Scheffer, Steven Petrou, Snezana Maljevic","doi":"10.1016/j.nbd.2024.106782","DOIUrl":"10.1016/j.nbd.2024.106782","url":null,"abstract":"<p><strong>Background: </strong>Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes. KCNQ2 encodes a voltage-gated potassium channel K_V7.2 widely expressed in the central nervous system and critically involved in the regulation of neuronal excitability. In this study, we aimed to characterise a KCNQ2 variant (K556E) found in a female patient with DEE using a heterologous expression system and a knock-in mouse model.</p><p><strong>Methods: </strong>Wild-type KCNQ2 or K556E variant were expressed in Chinese Hamster Ovary (CHO) cells (with or without KCNQ3) and their biophysical properties assessed using patch clamp recordings. We further engineered a new Kcnq2 DEE mouse model (K557E) based on the K556E variant and characterised it using behavioural, electrophysiological, and transcriptome analysis.</p><p><strong>Results: </strong>A mild loss of function was observed only when the mutant channel was co-expressed with KCNQ3 in the heterologous system. The heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (K_V7 channel opener) able to rescue both the increased sensitivity to chemically-induced seizures in vivo and neuronal excitability ex vivo. Whole-brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes.</p><p><strong>Conclusions: </strong>Our study reports on a novel Kcnq2 DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptome analysis providing insights into KCNQ2 DEE mechanisms that can be leveraged for future therapy development.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106782"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903495","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}

{"title":"Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1^+/- mice.","authors":"Colette Reinhold, Susanne Knorr, Rhonda L McFleder, Lisa Harder-Rauschenberger, Tom Gräfenhan, Andreas Schlosser, Michael Sendtner, Jens Volkmann, Chi Wang Ip","doi":"10.1016/j.nbd.2024.106783","DOIUrl":"10.1016/j.nbd.2024.106783","url":null,"abstract":"<p><p>DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1^+/-). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1^+/- mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1^+/- mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1^+/- mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1^+/- mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1^+/- and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1^+/- mice.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106783"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895660","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}

{"title":"Alpha-synuclein pathology enhances peripheral and CNS immune responses to bacterial endotoxins.","authors":"Anna-Sophia Hartke, Cara S Schreiber, Kristina Lau, Ivo Wiesweg, Inken Waltl, Ulrich Kalinke, Franziska Richter, Christopher Käufer","doi":"10.1016/j.nbd.2024.106773","DOIUrl":"10.1016/j.nbd.2024.106773","url":null,"abstract":"<p><p>Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxin is suggested as a risk factor, and LPS shedding gram-negative bacteria are more prevalent in the gut-microbiome of PD patients. Here, we investigated whether LPS could contribute to the neurodegenerative disease progression via neuroinflammation, especially under conditions of aSyn pathology. To investigate this, we created a double-hit model based on the Thy1-aSyn mouse line (line 61), an established aSyn-overexpression model of PD, exposed to a single intraperitoneal injection of LPS at a dose of 0.8 mg/kg (equivalent to approximately 1,200,000 EU/kg). Clinical parameters, flow cytometry of blood and immune cells in the brain, brain immunohistology and motor behavior were evaluated over time. As expected, the LPS dosage induced transient acute symptoms and mild weight loss in mice, with full recovery after 7 days. In aSyn over-expressing mice, this single low dose of LPS was sufficient to alter the expression of specific markers on blood and brain immune cells and induced brain region-specific microgliosis that were present at 7 days post LPS injection. At 14 days post injection of LPS, aSyn expression was reduced in wild-type mice, indicating a specific response of the endogenous protein to the endotoxin. At this early time point, motor behavior is not yet robustly impacted by the observed pathological alterations. In conclusion, aSyn pathology renders the peripheral and central immune response more sensitive to a single low dose of bacterial endotoxin, which mimics a transient dysbiosis or gut infection. Thus, this data suggests that such peripheral triggers should be monitored in PD patients for instance by blood immune cell response as biomarkers. Furthermore, results from this study lend further support to the development of treatments aiming to reduce the impact of bacterial dysbiosis as a promising strategy to mitigate PD progression.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106773"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877489","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}

{"title":"Anxiety-like behavior and altered hippocampal activity in a transgenic mouse model of Fabry disease.","authors":"Kai Kummer, Jeiny Luna Choconta, Marie-Luise Edenhofer, Archana Bajpai, Gopuraja Dharmalingam, Theodora Kalpachidou, David A Collier, Michaela Kress","doi":"10.1016/j.nbd.2025.106797","DOIUrl":"10.1016/j.nbd.2025.106797","url":null,"abstract":"<p><strong>Background: </strong>Fabry disease (FD) patients are known to be at high risk of developing neuropsychiatric symptoms such as anxiety, depression and cognitive deficits. Despite this, they are underdiagnosed and inadequately treated. It is unknown whether these symptoms arise from pathological glycosphingolipid deposits or from cerebrovascular abnormalities affecting neuronal functions in the central nervous system. We therefore aimed to fill this knowledge gap by exploring a transgenic FD mouse model with a combination of behavior, transcriptomic, functional and morphological assessments, with a particular focus on the hippocampus.</p><p><strong>Results: </strong>Male FD mice exhibited increased anxiety-like behavior in the open field test, accompanied by a reduced exploratory drive in the Barnes maze, which could be related to the increased deposition of globotriaosylceramide (Gb3) identified in the dentate gyrus (DG). Hippocampus single-cell sequencing further revealed that Gb3 accumulation was associated with differential gene expression in neuronal and non-neuronal cell populations with granule, excitatory and interneurons, as well as microglia and endothelial cells as the main clusters with the most dysregulated genes. Particularly FD hippocampal neurons showed decreased electrical baseline activity in the DG and increased activity in the CA3 region of acutely dissected hippocampal slices.</p><p><strong>Conclusions: </strong>Our study highlights transcriptional and functional alterations in non-neuronal and neuronal cell clusters in the hippocampus of FD mice, which are suggested to be causally related to anxiety-like behavior developing as a consequence of FD pathology in mouse models of the disease and in patients.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106797"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951655","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}

{"title":"Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors.","authors":"Brianne Dentel, Lidiette Angeles-Perez, Abigail Y Flores, Katherine Lei, Chongyu Ren, Andrea Pineda Sanchez, Peter T Tsai","doi":"10.1016/j.nbd.2025.106790","DOIUrl":"10.1016/j.nbd.2025.106790","url":null,"abstract":"<p><p>Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (Baldassari et al., 2018). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (Yuskaitis et al., 2018; Dentel et al., 2022); however, studies focused on understanding mechanisms contributing to NDD-relevant behaviors are lacking, especially studies understanding the contributions of GATOR1's critical GAP catalytic subunit, nitrogen permease regulator like-2 (Nprl2). Given the clinical phenotypes observed in patients with Nprl2 mutations, in this study, we sought to investigate the neuronal cell type contributions of Nprl2 to NDD behaviors. We conditionally deleted Nprl2 broadly in most neurons (Synapsin1^cre), in inhibitory neurons only (Vgat^cre), and in Purkinje cells within the cerebellum (L7^cre). Broad neuronal deletion of Nprl2 resulted in seizures, social and learning deficits, and hyperactivity. In contrast, deleting Nprl2 from inhibitory neurons led to increased motor learning, hyperactive behavior, in addition to social and learning deficits. Lastly, Purkinje cell (PC) loss of Nprl2 also led to learning and social deficits but did not affect locomotor activity. These phenotypes enhance understanding of the spectrum of disease found in human populations with GATOR1 loss of function and highlight the significance of distinct cellular populations to NDD-related behaviors. SIGNIFICANCE STATEMENT: We aim to elucidate the neuronal-specific contributions of nitrogen permease regulator like-2 (Nprl2) to its neurodevelopmental disorder (NDD)-relevant phenotypes. We conditionally deleted Nprl2 broadly in neurons (Syn1^cre), in inhibitory neurons (Vgat^cre), and in cerebellar Purkinje cells (L7^cre). We identify seizures only in the Syn1^cre conditional mutant (cKO); hyperactivity, learning difficulties, social deficits, and impulsivity in the Syn1^cre and Vgat^cre cKOs; and social deficits, and fear learning deficits in L7^cre cKOs. To our knowledge, we are the first to describe the behavioral contributions of Nprl2's function across multiple cell types. Our findings highlight both critical roles for Nprl2 in learning and behavior and also distinct contributions of select neuronal populations to these NDD-relevant behaviors.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"106790"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966037","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}