GABAA receptors as targets for treating affective and cognitive symptoms of depression

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 586 - 600

Published: Aug. 3, 2023

Language: Английский

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Astrocyte-secreted neurocan controls inhibitory synapse formation and function

Neuron, Journal Year: 2024, Volume and Issue: 112(10), P. 1657 - 1675.e10

Published: April 3, 2024

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an protein. After secretion from astrocytes, is cleaved into N- C-terminal fragments. We found these fragments have distinct localizations in extracellular matrix. The fragment localizes to controls cortical function. Neurocan knockout mice lacking whole protein or only its domain reduced numbers Through super-resolution microscopy, vivo proximity labeling TurboID, astrocyte-specific rescue approaches, discovered somatostatin-positive regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific mammalian brain.

Language: Английский

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The covariance environment defines cellular niches for spatial inference

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: April 2, 2024

A key challenge of analyzing data from high-resolution spatial profiling technologies is to suitably represent the features cellular neighborhoods or niches. Here we introduce covariance environment (COVET), a representation that leverages gene-gene covariate structure across cells in niche capture multivariate nature interactions within it. We define principled optimal transport-based distance metric between COVET niches scales millions cells. Using encode context, developed environmental variational inference (ENVI), conditional autoencoder jointly embeds and single-cell RNA sequencing into latent space. ENVI includes two decoders: one impute gene expression modality second project information onto data. can confer context genomics single dissociated outperforms alternatives for imputing on diverse datasets.

Language: Английский

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Expression and functions of adenylyl cyclases in the CNS

Fluids and Barriers of the CNS, Journal Year: 2022, Volume and Issue: 19(1)

Published: March 20, 2022

Abstract Adenylyl cyclases (ADCYs), by generating second messenger cAMP, play important roles in various cellular processes. Their expression, regulation and functions the CNS, however, remain largely unknown. In this review, we first introduce classification structure of ADCYs, followed a discussion mammalian ADCYs (ADCY1-10). Next, expression function each ADCY isoform are summarized region/cell-specific manner. Furthermore, effects GPCR-ADCY signaling on blood–brain barrier (BBB) integrity reviewed. Last, current challenges future directions discussed. We aim to provide succinct review foster new research future.

Language: Английский

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Neocortical somatostatin neuron diversity in cognition and learning

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Neuropeptide System Regulation of Prefrontal Cortex Circuitry: Implications for Neuropsychiatric Disorders

Frontiers in Neural Circuits, Journal Year: 2022, Volume and Issue: 16

Published: June 21, 2022

Neuropeptides, a diverse class of signaling molecules in the nervous system, modulate various biological effects including membrane excitability, synaptic transmission and synaptogenesis, gene expression, glial cell architecture function. To date, most what is known about neuropeptide action limited to subcortical brain structures tissue outside central system. Thus, there knowledge gap our understanding function within cortical circuits. In this review, we provide comprehensive overview families neuropeptides their cognate receptors that are expressed prefrontal cortex (PFC). Specifically, highlight dynorphin, enkephalin, corticotropin-releasing factor, cholecystokinin, somatostatin, Y, vasoactive intestinal peptide. Further, review implication circuit use as potential therapeutic targets. Together, summarizes established highlights unknowns modulation neural underlying while offering insights for future research. An increased emphasis area study necessary elucidate basic principles used circuits beyond fast excitatory inhibitory transmitters well consider components PFC target neurological disorders. Therefore, not only sheds light on importance studies, but also provides serve roadmap studies field.

Language: Английский

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Depressive patient‐derived GABA interneurons reveal abnormal neural activity associated with HTR2C

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 15(1)

Published: Nov. 14, 2022

Article14 November 2022Open Access Source DataTransparent process Depressive patient-derived GABA interneurons reveal abnormal neural activity associated with HTR2C Kaiqin Lu Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School Pharmacy, Nanjing Medical University, Nanjing, China Contribution: Data curation, Formal analysis, Funding acquisition, ​Investigation, Writing - original draft, Project administration, review & editing Search more papers by this author Yuan Hong orcid.org/0000-0002-4390-7353 Software, ​Investigation Mengdan Tao Luping Shen Zhilong Zheng Department Neurobiology, Human Functional Genomics Jiangsu Province, Methodology Kaiheng Fang Min Xu Resources, Methodology, administration Chun Wang Brain Hospital Affiliated to Dongya Zhu Xing Guo Corresponding Author [email protected] orcid.org/0000-0002-0216-0310 Co-innovation Center Neuroregeneration, Nantong Jiangsu, Yan Liu orcid.org/0000-0003-2918-5398 Supervision, Information Lu1,†, Hong1,†, Tao1,†, Shen1,†, Zheng2, Fang1, Yuan1, Xu1, Wang3, Zhu1, *,2,4 *,1 1Institute 2Department 3Nanjing 4Co-innovation † These authors contributed equally work *Corresponding author. Tel: +86 25 86869345; E-mail: 86868467; EMBO Mol Med (2023)15:e16364https://doi.org/10.15252/emmm.202216364 PDFDownload PDF article text main figures.PDF PLUSDownload text, figures, expanded view figures appendix. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Major depressive disorder suicide behavior (sMDD) is severe mood disorder, bringing tremendous burden family society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues sMDD patients, molecular mechanism which levels are altered remains elusive. In study, we generated induced pluripotent stem cells (iPSC) from five patients differentiated iPSCs GABAergic (GINs) ventral forebrain organoids. GINs exhibited neuronal morphology increased firing, as well weakened calcium signaling propagation, compared controls. Transcriptomic sequencing revealed that decreased expression serotoninergic receptor 2C (5-HT2C) may cause defected sMDD. Furthermore, targeting 5-HT2C receptor, using small molecule agonist or genetic approach, restored deficits GINs. Our findings provide human cellular model studying mechanisms drug discoveries Synopsis iPSC-derived major disorders exhibit expression. Trazodone hydrochloride (Trzd) targets restores deficits, indicating could be therapeutic target sMDD-derived display GIN subtypes. show electrophysiological hyperexcitability signaling. Transcriptional analysis reveals low sMDD-associated defects can overexpression 5-HT2CR Trzd. Introduction (MDD) leading disability, global prevalence 4.4–5.0% (WHO, 2017). Individuals MDD often loss pleasure, sleep disorders, mental disturbances (First et al, 2015). So far, pathogenesis elusive, at least partly due highly heterogeneity symptoms etiology. Thus, one subgroup MDD, such (sMDD), shares common symptom, open window revealing MDD. Severe who have committed pose serious families communities (Ferrari 2013). Neuroimaging studies reported subcortical brain structures (Krishnan Nestler, 2008; Murrough 2016; Belleau 2019) sMDD, volume dentate gyrus (DG) (MacQueen 2008) nerve growth factor (Wohleb 2016). Immunohistochemical evidence slices showed GABAB receptor-mediated inhibition dysregulated, suggesting were involved regulation glutamate-glutamine-GABA cycle suicidal individuals (Bernstein 2013; Lewis 2018). An integrative genomics study GABAA 2 (GABRG2), lower (Yin Also, female veterans behavior, ratio over creatine+ phosphocreatine anterior cingulate cortex was significantly (Prescot Some these biochemical changes, reduction transmission GABA-synthesizing enzyme 67 (GAD67) protein levels, GABAA/B animal models (Luscher 2011; Banasr 2017; Jacobson 2018; Duman 2019), hypothesis disrupted structural functional integrity prefrontal networks pathophysiological basis Clinically, elevating Brexanolone (SAGE-547) transcranial stimulation, developed antidepressant treatments (Kanes Heimrath 2020). However, whether system still unclear. it big challenge etiology potential drugs (Preti, Locci Pinna, 2019). Induced (iPSCs) derived neurological offer (Fujimori Differentiation iPSCs-derived bipolar (BD) into hippocampal gyrus-like neurons mitochondrial abnormalities excitation BD (Mertens two disease pathophysiology organoids psychiatric Fragile X syndrome (Wen 2014; Kang 2021). Two recent longer neurites serotonin-induced hyperactivity downstream upregulated excitatory serotonergic receptors respectively SSRI-resistant default (Vadodaria 2019a,b). provided discoveries. iPSC not reported. Here, attempted once patient-specific included We found subtype GINs, reversed an FDA-approved targeted receptors. Taken together, our current important phenotypes organoids, offering tool identifying approaches. Results neurite branches subtypes reprogrammed peripheral blood (SA004, SA005-1, SA005-3, SA006, SA007, SA008. Notably, SA005-1 SA005-3 same subject). parallel, used NC3-1, IMR90-4, RC01001-A, ihtc-03, RC01001-C lines controls (CTRLs, Figs 1A EV1A, Table EV1). The established expressed pluripotency markers, alkaline phosphatase (AP), SOX2, NANOG (Fig EV1B). Following differentiation (Stefansson 2003) protocol (Liu 2020) EV1C), both CTRL > 80% GABA+ among TUJ1+ day 35 1B C). proportion MAP2+ mature (ranging 69.91 81.54%) HO+ total 49.63 72.43%) EV1D–G). There no significant difference between different cell lines. Figure 1. Scheme illustrating generation (five CTRLs six patients). Representative images cultures showing TUJ1 Scale bar = 100 μm. 35. (CTRL, n 120 fields counted lines; 134 6 lines). Mean ± SEM. schematic morphometric Sholl 50 intersection number (Each red box lines, independently differentiations each point represents mean value independent experiments, 226 groups. Each blue 30 260 groups). Two-way ANOVA distance soma, ****P < 0.0001 10, center line shows median SEM whiskers represent maximum minimum. 65. Quantification primary branch numbers shown 65, ≥ 11, Nested t-test, **P 0.0016 versus median. longest length 0.0075 calretinin (CR) CR+ days 35, 40 50, respectively. (Red 5 line. timepoints, ns: 50. somatostatin (SST) co-staining neuron marker MAP2 SST+ 43 groups 37 T-test, 0.0001. data available online figure. 1 [emmm202216364-sup-0006-SDataFig1.zip] Download figure PowerPoint Click here expand EV1. Generation patients. Related Fig patients' mononuclear (PBMC). 250 (MEF, Mouse Embryonic Fibroblast). Alkaline staining immunostaining undifferentiated images. Schematic diagram left three pannels: scale right pannel: 15. HO 13.Mean intersections groups, sum ***P 0.0006 83 *P 0.0118 0.0027 stress-induced defect dendritic density (Qiao Zhao then examined 1D). increase concentric circles 30, μm soma 1E), interactions elevated, EV1H I), complexity next analyzed similar results 1F), intersections, EV1J K). measured 1G H). Previous suggested subtypes, (SST), related (Smiley Song To further analyze assessed CR 40, group (11.8 0.4%) fewer than (17.4 0.7%). population obtained (sMDD: 16.0 0.7%; CTRL: 28.3 1.2%) 1I J). At 1K L). Altogether, indicated One hypothesized impaired circuits (Duman performed whole-cell patch-clamp recording on 6-week-old measure intrinsic membrane properties 2A). Under voltage clamp, APs evoked injection range 10 60 pA readily CTRLs. AP amplitude frequency higher 2B–E). half-width ~56% narrower 2F), excessive channel activation (Bean, 2007; Paşca 2011). sodium potassium currents correlate APs. larger inward 2G), activated response depolarization CTRL. fast 30–80 mV markedly elevated 2H). Collectively, determine characteristics later stage, 70. Consistent 45, amplitudes EV2A–D), along EV2E–G). demonstrated 2. 45–60 A. representative recording. B. traces holding −70 (blue) (red) C. Average during 500 ms stepwise 55 0.01. D–F. Amplitude half width first 10-pA 0.01; 0.001. G. Traces Na+/K+ recorded average peak values Na+ 46 38 H. 36 ANOVA, 0.001; [emmm202216364-sup-0007-SDataFig2.zip] EV2. 70–80. method 23 0.05. D. Half P 0.0872. E, F. Sample 24 Calcium imaging reliable (de Melo Reis rodent studies, disturbance Ca2+ homeostasis signals (Ma 2019; investigate coupled changes depolarization, via fluorescence indicator dye Fluo-4 AM time-series microscopy 3A). After loaded onto cells, intracellular fluctuations monitored fluorescent intensity time mM KCL stimulation 3B). Then decrease [Ca2+]i rise following after 1-min continuous 3C). Next, statistical curve. Peak Ca2+(Fmax–F0)/F0, 2013), 3D). 3. Defects dyes. timepoint. 20 trajectory (red line) (blue KCL. CTRL, neurons; neurons. experiment (the whole quantification result D). [Ca2+] (Fmax–F0)/F0 per (n 155 198 0.0022 hiPS cells. Immunostaining interneuron GAD67, progenitor SOX2 prosencephalic NKX2.1 states. 156 four 88 0.0005 3

Language: Английский

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Somatostatin and Somatostatin-Containing Interneurons—From Plasticity to Pathology

Biomolecules, Journal Year: 2022, Volume and Issue: 12(2), P. 312 - 312

Published: Feb. 15, 2022

Despite the obvious differences in pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some them share general but pivotal mechanisms, one which is disruption excitation/inhibition balance. Such an imbalance can be generated by changes inhibitory system, very often mediated somatostatin-containing interneurons (SOM-INs). In physiology, this group interneurons, as well somatostatin itself, profoundly shapes brain activity, thus influencing behavior and plasticity; however, number, density activity SOM-INs levels are found throughout many neurological conditions, both patients animal models. Here, we (1) briefly describe somatostatinergic characterizing neuropeptide its receptors functions, physiology circuitry SOM-INs; (2) summarize effects physiological processes pathological focusing primarily on learning-induced plasticity encompassing selected neuropsychological respectively. The presented data indicate somatostatinergic-system-mediated inhibition a substantial factor mechanisms neuroplasticity, disrupted plethora pathologies.

Language: Английский

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In-silico EEG biomarkers of reduced inhibition in human cortical microcircuits in depression

PLoS Computational Biology, Journal Year: 2023, Volume and Issue: 19(4), P. e1010986 - e1010986

Published: April 10, 2023

Reduced cortical inhibition by somatostatin-expressing (SST) interneurons has been strongly associated with treatment-resistant depression. However, due to technical limitations it is impossible establish experimentally in humans whether the effects of reduced SST interneuron on microcircuit activity have signatures detectable clinically-relevant brain signals such as electroencephalography (EEG). To overcome these limitations, we simulated resting-state and EEG using detailed models human microcircuits normal (healthy) or (depression), found that depression exhibited increased theta, alpha low beta power (4–16 Hz). The changes involved a combination an aperiodic broadband periodic theta components. We then demonstrated specificity showing they were distinct from those corresponding parvalbumin-expressing (PV) inhibition. Our study thus links level features microcircuits, which can serve better identify mechanistic subtypes EEG, non-invasively monitor modulation

Language: Английский

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Identification and validation of oxidative stress and immune-related hub genes in Alzheimer’s disease through bioinformatics analysis

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Jan. 12, 2023

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in aged population. Oxidative stress and neuroinflammation play important roles pathogenesis AD. Investigation hub genes for development potential therapeutic targets candidate biomarkers warranted. The differentially expressed (DEGs) AD were screened GSE48350 dataset. oxidative (DEOSGs) analyzed by intersection DEGs stress-related genes. immune-related DEOSGs identified weighted gene co-expression network analysis (WGCNA) protein–protein interaction (PPI) analysis, respectively. Enrichment was performed Gene Ontology Kyoto Encyclopedia Genes Genomes. diagnostic value assessed receiver operating characteristic validated GSE1297. mRNA expression determined qRT-PCR analysis. Finally, we constructed drug, transcription factors (TFs), microRNA A total 1160 (259 up-regulated 901 down-regulated) GSE48350. Among them 111 Thereafter, significant difference infiltrated immune cells (effector memory CD8 T cell, activated B natural killer CD56 bright plasmacytoid dendritic neutrophil) between control samples. 27 modules obtained through WGCNA turquoise module most relevant module. We 66 intersecting with 15 PPI them, 9 (CCK, CNR1, GAD1, GAP43, NEFL, NPY, PENK, SST, TAC1) good values verified revealed downregulation CCK, PENK upregulation NEFL 76 agents, 152 miRNAs targets, 91 TFs regulatory networks. Our study key associated reaction pathogenesis. findings may help to provide promising

Language: Английский

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