Pub Date : 2026-01-01Epub Date: 2025-11-24DOI: 10.1016/j.pneurobio.2025.102856
Kirsten Bohmbach , Vincent Bauer , Christian Henneberger
Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.
神经元树突整合兴奋性输入。它们可以通过放大同步的局部输入和树突尖峰来执行局部计算，例如巧合检测。细胞外甘氨酸可以作为n -甲基- d -天冬氨酸（NMDA）亚型谷氨酸受体的协同激动剂，也可以作为抑制性甘氨酸受体（GlyRs）的配体，从而成为这一过程的强大调节剂。类似地，甘氨酸转运蛋白（GlyTs）是一种新兴的精神疾病和其他疾病的药物靶点，它可以通过环境甘氨酸水平控制树突整合。通过药理学分析甘氨酸、GlyTs和GlyRs如何改变局部树突兴奋性输入的突触后反应，在急性海马切片CA1锥体细胞的树突上验证了这两种假设。使用谷氨酸微离子电泳应用，我们发现甘氨酸确实可以显著增加树突的兴奋性和树突尖峰。我们还发现GlyTs是树突尖峰的强大调节剂，可以限制甘氨酸来源对CA1锥体细胞的影响。我们的实验还表明，GlyRs对缓慢的树突突成分具有相反的抑制作用。这直接表明甘氨酸可以动态增强树突对局部输入的响应性，促进树突尖峰，而GlyTs和GlyRs则相反。总之，这使得甘氨酸能信号成为CA1径向斜树突突触输入非线性整合的强大调制器。
{"title":"Glycine and glycine transport control dendritic excitability and spiking","authors":"Kirsten Bohmbach , Vincent Bauer , Christian Henneberger","doi":"10.1016/j.pneurobio.2025.102856","DOIUrl":"10.1016/j.pneurobio.2025.102856","url":null,"abstract":"<div><div>Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-<span>D</span>-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102856"},"PeriodicalIF":6.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145638142","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}
Pub Date : 2026-01-01Epub Date: 2025-12-04DOI: 10.1016/j.pneurobio.2025.102864
Mirte Scheper , Alessandro Gaeta , Gabriele Ruffolo , Lilian J. Lissner , Marie Le Bihan , Jasper J. Anink , Floor E. Jansen , Wim van Hecke , Angelika Mühlebner , Dirk Schubert , James D. Mills , Eleonora Palma , Eleonora Aronica
Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in Xenopus laevis oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.
{"title":"Altered somatostatin receptor 3 expression and functional dysregulation in tuberous sclerosis complex","authors":"Mirte Scheper , Alessandro Gaeta , Gabriele Ruffolo , Lilian J. Lissner , Marie Le Bihan , Jasper J. Anink , Floor E. Jansen , Wim van Hecke , Angelika Mühlebner , Dirk Schubert , James D. Mills , Eleonora Palma , Eleonora Aronica","doi":"10.1016/j.pneurobio.2025.102864","DOIUrl":"10.1016/j.pneurobio.2025.102864","url":null,"abstract":"<div><div>Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in <em>Xenopus laevis</em> oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102864"},"PeriodicalIF":6.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682970","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}
Pub Date : 2026-01-01Epub Date: 2025-12-03DOI: 10.1016/j.pneurobio.2025.102857
Andrea Sánchez Corzo , Esteban Bullón Tarrasó , Martina Saltafossi , Teresa Berther , Tobias Staudigl , Daniel S. Kluger , Thomas Schreiner
While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.
{"title":"Respiratory coordination of excitability states across the human wake-sleep cycle","authors":"Andrea Sánchez Corzo , Esteban Bullón Tarrasó , Martina Saltafossi , Teresa Berther , Tobias Staudigl , Daniel S. Kluger , Thomas Schreiner","doi":"10.1016/j.pneurobio.2025.102857","DOIUrl":"10.1016/j.pneurobio.2025.102857","url":null,"abstract":"<div><div>While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102857"},"PeriodicalIF":6.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682971","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}
Pub Date : 2026-01-01Epub Date: 2025-11-03DOI: 10.1016/j.pneurobio.2025.102844
Christos Panagiotis Lisgaras , Helen E. Scharfman
Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer’s disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250–500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1–500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.
{"title":"Opposing interictal dynamics in Alzheimer’s disease and epilepsy","authors":"Christos Panagiotis Lisgaras , Helen E. Scharfman","doi":"10.1016/j.pneurobio.2025.102844","DOIUrl":"10.1016/j.pneurobio.2025.102844","url":null,"abstract":"<div><div>Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer’s disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250–500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1–500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2<sup>-/-</sup>, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102844"},"PeriodicalIF":6.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452771","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}
Pub Date : 2025-12-01Epub Date: 2025-11-12DOI: 10.1016/j.pneurobio.2025.102853
Lucas Canto-de-Souza , Daniela Baptista-de-Souza , Cristiane Busnardo , Carlos C. Crestani
We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.
{"title":"Effects of oxytocin receptor ligands on anxiogenic-like effect, social avoidance and changes on medial prefrontal cortex oxytocin receptor expression evoked by chronic social defeat stress in rats","authors":"Lucas Canto-de-Souza , Daniela Baptista-de-Souza , Cristiane Busnardo , Carlos C. Crestani","doi":"10.1016/j.pneurobio.2025.102853","DOIUrl":"10.1016/j.pneurobio.2025.102853","url":null,"abstract":"<div><div>We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102853"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524211","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}
Pub Date : 2025-12-01Epub Date: 2025-11-07DOI: 10.1016/j.pneurobio.2025.102845
Patrycja Brzdąk , Katarzyna Lebida , Patrycja Droździel , Emilia Stefańczyk , Aleksandra Leszczyńska , Jerzy W. Mozrzymas
Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.
{"title":"D1-type dopamine receptors are critical for GABAergic synaptic plasticity in CA1 mouse hippocampal SST interneurons and pyramidal cells","authors":"Patrycja Brzdąk , Katarzyna Lebida , Patrycja Droździel , Emilia Stefańczyk , Aleksandra Leszczyńska , Jerzy W. Mozrzymas","doi":"10.1016/j.pneurobio.2025.102845","DOIUrl":"10.1016/j.pneurobio.2025.102845","url":null,"abstract":"<div><div>Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102845"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482798","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}
Pub Date : 2025-12-01Epub Date: 2025-11-16DOI: 10.1016/j.pneurobio.2025.102854
Courtney Lane-Donovan , Mercedes Paredes , Aimee W. Kao
In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs—development and aging—that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (GBA: Gaucher’s disease and Parkinson’s disease), progranulin (GRN: neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (TSC1: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as “Lysosomal Clearance Disorders.”
{"title":"The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases","authors":"Courtney Lane-Donovan , Mercedes Paredes , Aimee W. Kao","doi":"10.1016/j.pneurobio.2025.102854","DOIUrl":"10.1016/j.pneurobio.2025.102854","url":null,"abstract":"<div><div>In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs—development and aging—that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (<em>GBA</em>: Gaucher’s disease and Parkinson’s disease), progranulin (<em>GRN:</em> neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (<em>TSC1</em>: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as “Lysosomal Clearance Disorders.”</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102854"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550252","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}
Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored.
Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration.
We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior.
Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.
{"title":"Inhibiting the JAK-STAT3 pathway in nucleus accumbens astrocytes alleviates cocaine-induced motor hyperactivity","authors":"Isabelle Arnoux , Anna Capano , Rachida Yakoubi , Claire Boulogne , Pascal Ezan , Carole Escartin , Nathalie Rouach","doi":"10.1016/j.pneurobio.2025.102852","DOIUrl":"10.1016/j.pneurobio.2025.102852","url":null,"abstract":"<div><div>Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored.</div><div>Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration.</div><div>We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior.</div><div>Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102852"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506557","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}
Pub Date : 2025-12-01Epub Date: 2025-11-16DOI: 10.1016/j.pneurobio.2025.102855
Vittoria Spero , Sabrina D’Amelio , Sonia Eligini , Raffaella Molteni , Cristina Banfi , Maria Grazia Cattaneo
Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called "residual symptoms", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (e.g., cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.
{"title":"The neurobiology of major depressive disorder: Updates and perspectives from proteomics","authors":"Vittoria Spero , Sabrina D’Amelio , Sonia Eligini , Raffaella Molteni , Cristina Banfi , Maria Grazia Cattaneo","doi":"10.1016/j.pneurobio.2025.102855","DOIUrl":"10.1016/j.pneurobio.2025.102855","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called \"residual symptoms\", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (<em>e.g.,</em> cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102855"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550279","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}
Pub Date : 2025-12-01Epub Date: 2025-10-25DOI: 10.1016/j.pneurobio.2025.102843
Sigurd L. Alnes , Ellen van Maren , Camille G. Mignardot , Ida Boccalaro , Thea Waldleben , Debora Ledergerber , Lennart H. Stieglitz , Markus Schmidt , Antoine Adamantidis , Lukas L. Imbach , Kaspar Schindler , Maxime O. Baud , Athina Tzovara
Auditory stimulation during non rapid eye movement (NREM) sleep has sparked remarkable interest for neuromodulation of sleep and improvement of memory and cognition. Yet, the electrophysiology of auditory brain responses in sleep remains elusive. Here, we studied auditory processing in the temporal lobe in humans using invasive electroencephalography recordings. We found that the auditory response hierarchy of wakefulness weakens during NREM sleep. NREM sleep instead exhibits two types of responses: (a) intracranial event-related potentials in the lateral and medial temporal lobe that are modulated by slow wave activity and are stronger and faster when sounds occur at or after the peak of local slow waves; (b) high-frequency responses in the temporal cortex, a proxy for neural firing, which are not affected by slow waves. These findings show slow wave resilient and slow wave dependent mechanisms for monitoring the environment during sleep and can drive future interventions based on auditory stimulation.
{"title":"Auditory responses in the temporal lobe are modulated by slow waves of sleep","authors":"Sigurd L. Alnes , Ellen van Maren , Camille G. Mignardot , Ida Boccalaro , Thea Waldleben , Debora Ledergerber , Lennart H. Stieglitz , Markus Schmidt , Antoine Adamantidis , Lukas L. Imbach , Kaspar Schindler , Maxime O. Baud , Athina Tzovara","doi":"10.1016/j.pneurobio.2025.102843","DOIUrl":"10.1016/j.pneurobio.2025.102843","url":null,"abstract":"<div><div>Auditory stimulation during non rapid eye movement (NREM) sleep has sparked remarkable interest for neuromodulation of sleep and improvement of memory and cognition. Yet, the electrophysiology of auditory brain responses in sleep remains elusive. Here, we studied auditory processing in the temporal lobe in humans using invasive electroencephalography recordings. We found that the auditory response hierarchy of wakefulness weakens during NREM sleep. NREM sleep instead exhibits two types of responses: (a) intracranial event-related potentials in the lateral and medial temporal lobe that are modulated by slow wave activity and are stronger and faster when sounds occur at or after the peak of local slow waves; (b) high-frequency responses in the temporal cortex, a proxy for neural firing, which are not affected by slow waves. These findings show slow wave resilient and slow wave dependent mechanisms for monitoring the environment during sleep and can drive future interventions based on auditory stimulation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102843"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145435520","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}
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