2025
Santoro, Elías Mateo Fernández, Landsmeer, Lennart P. L., Hamdioui, Said, Strydis, Christos, de Zeeuw, Chris I., Badura, Aleksandra, Negrello, Mario
Homeostatic bidirectional plasticity in upbound and downbound micromodules in a model of the olivocerebellar loop Journal Article
In: PLOS Computational Biology, vol. 21, iss. 10, 2025.
Abstract | Links | BibTeX | Tags:
@article{nokey,
title = {Homeostatic bidirectional plasticity in upbound and downbound micromodules in a model of the olivocerebellar loop},
author = {Elías Mateo Fernández Santoro and Lennart P.L. Landsmeer and Said Hamdioui and Christos Strydis and Chris I. de Zeeuw and Aleksandra Badura and Mario Negrello},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1013609},
doi = {10.1371/journal.pcbi.1013609},
year = {2025},
date = {2025-10-21},
urldate = {2025-10-21},
journal = {PLOS Computational Biology},
volume = {21},
issue = {10},
abstract = {Olivocerebellar learning is highly adaptable, unfolding over minutes to weeks depending on the task. However, the stabilizing mechanisms of the synaptic dynamics necessary for ongoing learning remain unclear. We constructed a model to examine plasticity dynamics under stochastic input and investigate the impact of inferior olive (IO) reverberations on Purkinje cell (PCs) activity and synaptic plasticity. We explored Upbound and Downbound cerebellar micromodules, which are organized loops of IO neurons, cerebellar nuclei neurons and microzones of PCs characterized by their unique molecular profiles and different levels of baseline firing. Our findings show synaptic weight convergence followed by stability of synaptic weights. In line with their relatively low and high intrinsic firing, we observed that Upbound and Downbound PCs have a propensity for potentiation and depression, respectively, with both PC types reaching stability at differential levels of overall strength of their parallel-fiber (PF) inputs. The oscillations and coupling of IO neurons participating in the Upbound and Downbound modules determine at which frequency band PFs can be stabilized optimally. Our results indicate that specific frequency components drive IO resonance and synchronicity, which, in turn, regulate temporal patterning across Upbound and Downbound zones, orchestrating their plasticity dynamics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Olivocerebellar learning is highly adaptable, unfolding over minutes to weeks depending on the task. However, the stabilizing mechanisms of the synaptic dynamics necessary for ongoing learning remain unclear. We constructed a model to examine plasticity dynamics under stochastic input and investigate the impact of inferior olive (IO) reverberations on Purkinje cell (PCs) activity and synaptic plasticity. We explored Upbound and Downbound cerebellar micromodules, which are organized loops of IO neurons, cerebellar nuclei neurons and microzones of PCs characterized by their unique molecular profiles and different levels of baseline firing. Our findings show synaptic weight convergence followed by stability of synaptic weights. In line with their relatively low and high intrinsic firing, we observed that Upbound and Downbound PCs have a propensity for potentiation and depression, respectively, with both PC types reaching stability at differential levels of overall strength of their parallel-fiber (PF) inputs. The oscillations and coupling of IO neurons participating in the Upbound and Downbound modules determine at which frequency band PFs can be stabilized optimally. Our results indicate that specific frequency components drive IO resonance and synchronicity, which, in turn, regulate temporal patterning across Upbound and Downbound zones, orchestrating their plasticity dynamics.
Negwer, Moritz, van der Werf, Ilse, Oudakker, Astrid, van Bokhoven, Hans, Schubert, Dirk, Kasri, Nael Nadif
BioRxiv preprint, 2025.
Abstract | Links | BibTeX | Tags:
@unpublished{nokey,
title = {Whole-brain clearing reveals region- and cell type-specific imbalances in inhibitory neurons in a mouse model for Kleefstra Syndrome},
author = {Moritz Negwer and Ilse van der Werf and Astrid Oudakker and Hans van Bokhoven and Dirk Schubert and Nael Nadif Kasri},
doi = {10.1101/2025.09.15.676416},
year = {2025},
date = {2025-09-16},
urldate = {2025-09-16},
abstract = {GABAergic inhibition is essential for balanced brain function and is frequently disrupted in neurodevelopmental disorders such as autism spectrum disorder (ASD). The inhibition is generated by a diverse population of GABAergic interneurons, which differ in subtype composition and spatial density across the brain. Here, we applied an unbiased whole-brain clearing and light-sheet imaging approach to systematically map the distribution of the three major GABAergic interneuron subtypes – Parvalbumin-positive (PV⁺), Somatostatin-positive (SST⁺), and Vasoactive Intestinal Polypeptide-positive (VIP⁺) cells – across the mouse brain in a model of Kleefstra Syndrome ( Ehmt1 +/− ), a monogenic intellectual disability disorder with a strong ASD component. Analyzing 895 brain regions we identified widespread, cell type– and region-specific alterations in GABAergic populations. Notably, we observed increased VIP⁺ neuron density in the Ehmt1 +/− cortex and decreased SST⁺ neuron density in sensory cortical and subcortical regions. In the basolateral amygdala (BLA), PV⁺ interneurons exhibited precocious maturation already at the juvenile stage, which persisted into adulthood and was associated with enhanced inhibitory input onto BLA principal neurons. We here demonstrate that Ehmt1 haploinsufficiency results in region– and cell-type specific changes throughout the brain. These results underscore the value of whole-brain, high-resolution mapping approaches in uncovering previously unrecognized patterns of neural vulnerability in neurodevelopmental disorders.},
howpublished = {BioRxiv preprint},
keywords = {},
pubstate = {published},
tppubtype = {unpublished}
}
GABAergic inhibition is essential for balanced brain function and is frequently disrupted in neurodevelopmental disorders such as autism spectrum disorder (ASD). The inhibition is generated by a diverse population of GABAergic interneurons, which differ in subtype composition and spatial density across the brain. Here, we applied an unbiased whole-brain clearing and light-sheet imaging approach to systematically map the distribution of the three major GABAergic interneuron subtypes – Parvalbumin-positive (PV⁺), Somatostatin-positive (SST⁺), and Vasoactive Intestinal Polypeptide-positive (VIP⁺) cells – across the mouse brain in a model of Kleefstra Syndrome ( Ehmt1 +/− ), a monogenic intellectual disability disorder with a strong ASD component. Analyzing 895 brain regions we identified widespread, cell type– and region-specific alterations in GABAergic populations. Notably, we observed increased VIP⁺ neuron density in the Ehmt1 +/− cortex and decreased SST⁺ neuron density in sensory cortical and subcortical regions. In the basolateral amygdala (BLA), PV⁺ interneurons exhibited precocious maturation already at the juvenile stage, which persisted into adulthood and was associated with enhanced inhibitory input onto BLA principal neurons. We here demonstrate that Ehmt1 haploinsufficiency results in region– and cell-type specific changes throughout the brain. These results underscore the value of whole-brain, high-resolution mapping approaches in uncovering previously unrecognized patterns of neural vulnerability in neurodevelopmental disorders.
de Kater, Sam, Herstel, Lotte J., Wieringa, Corette J.
Monitoring Changes in Intracellular Chloride Levels Using the FRET-Based SuperClomeleon Sensor in Organotypic Hippocampal Slices Journal Article
In: Bio-protocol, vol. 15, iss. 5, no. 5, 2025.
Abstract | Links | BibTeX | Tags:
@article{nokey,
title = {Monitoring Changes in Intracellular Chloride Levels Using the FRET-Based SuperClomeleon Sensor in Organotypic Hippocampal Slices},
author = {Sam de Kater and Lotte J. Herstel and Corette J. Wieringa},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC11896781/},
doi = {10.21769/BioProtoc.5229},
year = {2025},
date = {2025-03-05},
urldate = {2025-03-05},
journal = {Bio-protocol},
volume = {15},
number = {5},
issue = {5},
abstract = {The reduction in intracellular neuronal chloride concentration is a crucial event during neurodevelopment that
shifts GABAergic signaling from depolarizing to hyperpolarizing. Alterations in chloride homeostasis are
implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Recent
advancements in biosensor technology allow the simultaneous determination of intracellular chloride
concentration of multiple neurons. Here, we describe an optimized protocol for the use of the ratiometric
chloride sensor SuperClomeleon (SClm) in organotypic hippocampal slices. We record chloride levels as
fluorescence responses of the SClm sensor using two-photon microscopy. We discuss how the SClm sensor can
be effectively delivered to specific cell types using virus-mediated transduction and describe the calibration
procedure to determine the chloride concentration from SClm sensor responses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The reduction in intracellular neuronal chloride concentration is a crucial event during neurodevelopment that
shifts GABAergic signaling from depolarizing to hyperpolarizing. Alterations in chloride homeostasis are
implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Recent
advancements in biosensor technology allow the simultaneous determination of intracellular chloride
concentration of multiple neurons. Here, we describe an optimized protocol for the use of the ratiometric
chloride sensor SuperClomeleon (SClm) in organotypic hippocampal slices. We record chloride levels as
fluorescence responses of the SClm sensor using two-photon microscopy. We discuss how the SClm sensor can
be effectively delivered to specific cell types using virus-mediated transduction and describe the calibration
procedure to determine the chloride concentration from SClm sensor responses.
shifts GABAergic signaling from depolarizing to hyperpolarizing. Alterations in chloride homeostasis are
implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Recent
advancements in biosensor technology allow the simultaneous determination of intracellular chloride
concentration of multiple neurons. Here, we describe an optimized protocol for the use of the ratiometric
chloride sensor SuperClomeleon (SClm) in organotypic hippocampal slices. We record chloride levels as
fluorescence responses of the SClm sensor using two-photon microscopy. We discuss how the SClm sensor can
be effectively delivered to specific cell types using virus-mediated transduction and describe the calibration
procedure to determine the chloride concentration from SClm sensor responses.
2024
Santoro, Elías Mateo Fernández, Karim, Arun, Warnaar, Pascal, de Zeeuw, Chris I., Badura, Aleksandra, Negrello, Mario
Purkinje cell models: past, present and future Journal Article
In: Frontiers in Computational Neuroscience, vol. 18, 2024.
Abstract | Links | BibTeX | Tags:
@article{nokey,
title = {Purkinje cell models: past, present and future},
author = {Elías Mateo Fernández Santoro and Arun Karim and Pascal Warnaar and Chris I. de Zeeuw and Aleksandra Badura and Mario Negrello},
url = {https://www.frontiersin.org/journals/computational-neuroscience/articles/10.3389/fncom.2024.1426653/full},
doi = {10.3389/fncom.2024.1426653},
year = {2024},
date = {2024-07-10},
urldate = {2024-07-10},
journal = {Frontiers in Computational Neuroscience},
volume = {18},
abstract = {The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70′s, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70′s, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.